Human protein tyrosine phosphatase inhibitors an methods of use

ABSTRACT

The present disclosure relates to compounds effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors thereby regulating angiogenesis. The present disclosure further relates to compositions comprising said human protein tyrosine phosphatase beta (HPTP-β) inhibitors, and to methods for regulating angiogenesis.

PRIORITY

This application claims the benefit of Provisional Application Ser. No.60/816,730 filed on Jun. 27, 2006. The entire disclosure of thisapplication is incorporated herein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to compounds effective as human proteintyrosine phosphatase beta (HPTP-β) inhibitors thereby regulatingangiogenesis. The present disclosure further relates to compositionscomprising said human protein tyrosine phosphatase beta (HPTP-β)inhibitors, and to methods for regulating angiogenesis.

BACKGROUND OF THE DISCLOSURE

Angiogenesis, the sprouting of new blood vessels from the pre-existingvasculature, plays a crucial role in a wide range of physiological andpathological processes (Nguyen, L. L. et al., Int. Rev. Cytol., 204,1-48, (2001)). Angiogenesis is a complex process, mediated bycommunication between the endothelial cells that line blood vessels andtheir surrounding environment. In the early stages of angiogenesis,tissue or tumor cells produce and secrete pro-angiogenic growth factorsin response to environmental stimuli such as hypoxia. These factorsdiffuse to nearby endothelial cells and stimulate receptors that lead tothe production and secretion of proteases that degrade the surroundingextracellular matrix. The activated endothelial cells begin to migrateand proliferate into the surrounding tissue toward the source of thesegrowth factors (Bussolino, F., Trends Biochem. Sci., 22, 251-256,(1997)). Endothelial cells then stop proliferating and differentiateinto tubular structures, which is the first step in the formation ofstable, mature blood vessels. Subsequently, periendothelial cells, suchas pericytes and smooth muscle cells, are recruited to the newly formedvessel in a further step toward vessel maturation.

Angiogenesis is regulated by a balance of naturally occurring pro- andanti-angiogenic factors. Vascular endothelial growth factor, fibroblastgrowth factor, and angiopoeitin represent a few of the many potentialpro-angiogenic growth factors. These ligands bind to their respectivereceptor tyrosine kinases on the endothelial cell surface and transducesignals that promote cell migration and proliferation. Whereas manyregulatory factors have been identified, the molecular mechanisms ofthis process are still not fully understood.

There are many disease states driven by persistent unregulated orimproperly regulated angiogenesis. In such disease states, unregulatedor improperly regulated angiogenesis may either cause a particulardisease or exacerbate an existing pathological condition. For example,ocular neovascularization has been implicated as the most common causeof blindness and underlies the pathology of approximately 20 eyediseases. In certain previously existing conditions such as arthritis,newly formed capillary blood vessels invade the joints and destroycartilage. In diabetes, new capillaries formed in the retina invade thevitreous humor, causing bleeding and blindness. Both the growth andmetastasis of solid tumors are also angiogenesis-dependent (Folkman etal., “Tumor Angiogenesis,” Chapter 10, 206-32, in The Molecular Basis ofCancer, Mendelsohn et al., eds., W.B. Saunders, (1995)). It has beenshown that tumors which enlarge to greater than 2 mm in diameter mustobtain their own blood supply and do so by inducing the growth of newcapillary blood vessels. After these new blood vessels become embeddedin the tumor, they provide nutrients and growth factors essential fortumor growth as well as a means for tumor cells to enter the circulationand metastasize to distant sites, such as liver, lung or bone (Weidner,New Eng. J. Med., 324, 1, 1-8 (1991)). When used as drugs intumor-bearing animals, natural inhibitors of angiogenesis may preventthe growth of small tumors (O'Reilly et al., Cell, 79, 315-28 (1994)).In some protocols, the application of such inhibitors leads to tumorregression and dormancy even after cessation of treatment (O'Reilly etal., Cell, 88, 277-85 (1997)). Moreover, supplying inhibitors ofangiogenesis to certain tumors may potentiate their response to othertherapeutic regimens (Teischer et al., Int. J. Cancer, 57, 920-25(1994)).

Although many disease states are driven by persistent unregulated orimproperly regulated angiogenesis, some disease states could be treatedby increased angiogenesis. Tissue growth and repair are biologic eventswherein cellular proliferation and angiogenesis occur. Thus an importantaspect of wound repair is the revascularization of damaged tissue byangiogenesis.

Chronic, non-healing wounds are a major cause of prolonged morbidity inthe aged human population. This is especially the case in bedridden ordiabetic patients who develop severe, non-healing skin ulcers. In manyof these cases, the delay in healing is a result of inadequate bloodsupply either as a result of continuous pressure or of vascularblockage. Poor capillary circulation due to small artery atherosclerosisor venous stasis contributes to the failure to repair damaged tissue.Such tissues are often infected with microorganisms that proliferateunchallenged by the innate defense systems of the body which requirewell vascularized tissue to effectively eliminate pathogenic organisms.As a result, most therapeutic intervention centers on restoring bloodflow to ischemic tissues thereby allowing nutrients and immunologicalfactors access to the site of the wound.

Atherosclerotic lesions in large vessels may cause tissue ischemia thatcould be ameliorated by modulating blood vessel growth to the affectedtissue. For example, atherosclerotic lesions in the coronary arteriesmay cause angina and myocardial infarction that could be prevented ifone could restore blood flow by stimulating the growth of collateralarteries. Similarly, atherosclerotic lesions in the large arteries thatsupply the legs may cause ischemia in the skeletal muscle that limitsmobility and in some cases necessitates amputation, which may also beprevented by improving blood flow with angiogenic therapy.

Other diseases such as diabetes and hypertension are characterized by adecrease in the number and density of small blood vessels such asarterioles and capillaries. These small blood vessels are important forthe delivery of oxygen and nutrients. A decrease in the number anddensity of these vessels contributes to the adverse consequences ofhypertension and diabetes including claudication, ischemic ulcers,accelerated hypertension, and renal failure. These common disorders andmany other less common ailments, such as Burgers disease, could beameliorated by increasing the number and density of small blood vesselsusing angiogenic therapy.

It has been suggested that one means for regulating angiogenesis is totreat patients with a human protein tyrosine phosphatase beta (HPTP-β)inhibitor (Kruegar et al., EMBO J., 9, (1990)) and, therefore, tosatisfy this need the compounds of the present disclosure have beenprepared.

SUMMARY OF THE DISCLOSURE

The compounds of the present disclosure are a new class of compoundsthat can regulate angiogenesis in humans.

The present disclosure further relates to pharmaceutical compositionsand their pharmaceutically acceptable salts, and/or pharmaceuticalcompositions thereof comprising

-   -   a) an effective amount of one or more compounds according to the        present disclosure; and    -   b) an excipient . . . .

The present disclosures also relate to methods for controllingangiogenesis, and thereby providing a treatment for diseases affected byangiogenesis, said methods comprising administering to a human aneffective amount of a compound according to the present disclosure.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present disclosure.

DETAILED DESCRIPTION OF THE DISCLOSURE

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings:

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the relevant active compoundwithout causing clinically unacceptable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained.

Throughout the description and claims of this specification the word“comprise” and other forms of the word, such as “comprising” and“comprises,” means including but not limited to, and is not intended toexclude, for example, other additives, components, integers, or steps.

As used in the description and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a composition”includes mixtures of two or more such compositions.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that when a value is disclosed, then“less than or equal to” the value, “greater than or equal to the value,”and possible ranges between values are also disclosed, as appropriatelyunderstood by the skilled artisan. For example, if the value “10” isdisclosed, then “less than or equal to 10” as well as “greater than orequal to 10” is also disclosed. It is also understood that throughoutthe application data are provided in a number of different formats andthat this data represent endpoints and starting points and ranges forany combination of the data points. For example, if a particular datapoint “10” and a particular data point “15” are disclosed, it isunderstood that greater than, greater than or equal to, less than, lessthan or equal to, and equal to 10 and 15 are considered disclosed aswell as between 10 and 15. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 aredisclosed, then 11, 12, 13, and 14 are also disclosed.

The term “organic unit” as described herein refers to groups or moietiesthat comprise one or more carbon atoms and which form a portion of oneof the compounds or pharmaceutically acceptable salts thereof. Forexample, many of the substituent units referred to elsewhere herein areorganic units. In order to effectively function in the context of theirpresence in the compounds and/or salts disclosed herein, the organicunits should often have variable ranges of restricted size and/ormolecular weight, so as to provide desired binding to the targetenzymes, solubility, bioabsorption characteristics. For example, organicunit can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms. Organic units oftenhave hydrogen bound to at least some of the carbon atoms of the organicunits, and can optionally contain the common heteroatoms found insubstituted organic compounds, such as oxygen, nitrogen, sulfur, and thelike, or inorganic atoms such as halogens, phosphorus, and the like. Oneexample, of an organic radical that comprises no inorganic atoms is a5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments, an organicradical can contain 1-10 inorganic heteroatoms bound thereto or therein,including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.Examples of organic radicals include but are not limited to an alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substitutedamino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido,substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclicradicals, wherein the terms are defined elsewhere herein. A fewnon-limiting examples of organic radicals that include heteroatomsinclude alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals,dimethylamino radicals and the like.

Substituted and unsubstituted linear, branched, or cyclic alkyl unitsinclude the following non-limiting examples: methyl (C₁), ethyl (C₂),n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃), n-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄),cyclopentyl (C₅), cyclohexyl (C₆), and the like; whereas substitutedlinear, branched, or cyclic alkyl, non-limiting examples of whichincludes, hydroxymethyl (C₁), chloromethyl (C₁), trifluoromethyl (C₁),aminomethyl (C₁), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),1,2-difluoroethyl (C₂), 2,2,2-trifluoroethyl (C₃), 3-carboxypropyl (C₃),2,3-dihydroxycyclobutyl (C₄), and the like.

Substituted and unsubstituted linear, branched, or cyclic alkenylinclude, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),buten-4-yl (C₄), and the like; substituted linear or branched alkenyl,non-limiting examples of which include, 2-chloroethenyl (also2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl (C₄),7-hydroxy-7-methyloct-4-en-2-yl (C₉),7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like.

Substituted and unsubstituted linear or branched alkynyl include,ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃), propyn-1-yl (C₃), and2-methyl-hex-4-yn-1-yl (C₇); substituted linear or branched alkynyl,non-limiting examples of which include, 5-hydroxy-5-methylhex-3-ynyl(C₇), 6-hydroxy-6-methylhept-3-yn-2-yl (C₈),5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like.

Substituted and unsubstituted “alkoxy” are used herein denotes a unithaving the general formula —OR¹⁰⁰ wherein R¹⁰⁰ is an alkyl, alkylenyl,or alkynyl unit as defined herein above, for example, methoxy,methoxymethyl, methoxymethyl.

Substituted and unsubstituted “haloalkyl” are used herein denotes analkyl unit having a hydrogen atom substituted by one or more halogenatoms, for example, trifluoromethyl, 1,2-dichloroethyl, and3,3,3-trifluoropropyl.

The term “aryl” as used herein denotes cyclic organic units thatcomprise at least one benzene ring having a conjugated and aromaticsix-membered ring, non-limiting examples of which include phenyl (C₆),naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀). Aryl rings can have one ormore hydrogen atoms substituted by another organic or inorganic radical.Non-limiting examples of substituted aryl rings include: 4-fluorophenyl(C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆), 2-amino-4-fluorophenyl(C₆), 2-(N,N-diethylamino)phenyl (C₆), 2-cyanophenyl (C₆),2,6-di-tert-butylphenyl (C₆), 3-methoxyphenyl (C₆),8-hydroxynaphthylen-2-yl (C₁₀), 4,5-dimethoxynaphthylen-1-yl (C₁₀), and6-cyanonaphthylen-1-yl (C₁₀).

The term “heteroaryl” denotes an organic unit comprising a five or sixmember conjugated and aromatic ring wherein at least one of the ringatoms is a heteroatom selected from nitrogen, oxygen, or sulfur. Theheteroaryl rings can comprise a single ring, for example, a ring having5 or 6 atoms wherein at least one ring atom is a heteroatom not limitedto nitrogen, oxygen, or sulfur, such as a pyridine ring, a furan ring,or thiofuran ring. A “heteroaryl” can also be a fused multicyclic andheteroaromatic ring system having wherein at least one of the rings isan aromatic ring and at least one atom of the aromatic ring is aheteroatom including nitrogen, oxygen, or sulfur

The following are non-limiting examples of heteroaryl rings according tothe present disclosure:

The term “heterocyclic” denotes a ring system having from 3 to 10 atomswherein at least one of the ring atoms is a heteroatom not limited tonitrogen, oxygen, or sulfur. The rings can be single rings, fused rings,or bicyclic rings. Non-limiting examples of heterocyclic rings include:

All of the aforementioned heteroaryl or heterocyclic rings can beoptionally substituted with one or more substitutes for hydrogen asdescribed herein further.

Throughout the description of the present disclosure the terms havingthe spelling “thiophene-2-yl and thiophene-3-yl” are used to describethe heteroaryl units having the respective formulae:

whereas in naming the compounds of the present disclosure, the chemicalnomenclature for these moieties are typically spelled “thiophen-2-yl andthiophen-3-yl” respectively. Herein the terms “thiophene-2-yl andthiophene-3-yl” are used when describing these rings as units ormoieties which make up the compounds of the present disclosure solely tomake it unambiguous to the artisan of ordinary skill which rings arereferred to herein.

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as “a hydrocarbyl moiety, whetheracyclic or cyclic, which has one or more hydrogen atoms replaced by asubstituent or several substituents as defined herein below.” The units,when substituting for hydrogen atoms are capable of replacing onehydrogen atom, two hydrogen atoms, or three hydrogen atoms of ahydrocarbyl moiety at a time. In addition, these substituents canreplace two hydrogen atoms on two adjacent carbons to form saidsubstituent, new moiety, or unit. For example, a substituted unit thatrequires a single hydrogen atom replacement includes halogen, hydroxyl,and the like. A two hydrogen atom replacement includes carbonyl,oximino, and the like. A two hydrogen atom replacement from adjacentcarbon atoms includes epoxy, and the like. A three hydrogen replacementincludes cyano, and the like. The term substituted is used throughoutthe present specification to indicate that a hydrocarbyl moiety, interalia, aromatic ring, alkyl chain; can have one or more of the hydrogenatoms replaced by a substituent. When a moiety is described as“substituted” any number of the hydrogen atoms may be replaced. Forexample, 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring”,(N,N-dimethyl-5-amino)octanyl is a “substituted” C8 alkyl unit,3-guanidinopropyl is a “substituted C₃ alkyl unit,” and2-carboxypyridinyl is a “substituted heteroaryl unit.”

The following are non-limiting examples of units which can substitutefor hydrogen atoms on a hydrocarbyl or other unit:

-   -   i) C₁-C₁₂ linear, branched, or cyclic alkyl, alkenyl, and        alkynyl; for example, methyl (C₁), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C3), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein;    -   iv) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein below;    -   v) —(CR^(13a)R^(13b))_(z)OR²; for example, —OH, —CH₂OH, —OCH₃,        —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vi) —(CR^(13a)R^(13b))_(z)C(O)R¹²; for example, —COCH₃,        —CH₂COCH₃, —OCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   vii)-(CR^(13a)R^(13b))_(z)C(O)OR¹²; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   viii) —(CR^(13a)R^(13b))C(O)N(R²)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   ix) —(CR^(13a)R^(13b))_(z)N(R¹²)₂; for example, —NH₂, —CH₂NH₂,        —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃), —CH₂NHCH₃, —CH₂N(CH₃)₂, and        —CH₂NH(CH₂CH₃);    -   x) halogen; —F, —Cl, —Br, and —I;    -   xi) —(CR^(13a)R^(13b))_(z)CN;    -   xii) —(CR^(13a)R^(13b))_(z)NO₂;    -   xiii) —CH_(j)X_(k); wherein X is halogen, j is from 0 to 2,        j+k=3; for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   xiv) —(CR^(13a)R^(13b))_(z)SR¹²; —SH, —CH₂SH, —SCH₃, —CH₂SCH₃,        —SC₆H₅, and —CH₂SC₆H₅;    -   xv) —(CR^(13a)R^(13b))_(z)SO₂R¹²; —SO₂H, —CH₂SO₂H, —SO₂CH₃,        —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xiii) —(CR^(13a)R^(13b))_(z)SO₃R¹²; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R¹² is independently hydrogen, substituted or        unsubstituted C₁-C₄ linear, branched, or cyclic alkyl, phenyl,        benzyl; or two R¹² units can be taken together to form a ring        comprising 3-7 atoms; R^(13a) and R^(13b) are each independently        hydrogen or C₁-C₄ linear or branched alkyl; the index p is from        0 to 4.

For the purposes of the present disclosure the terms “compound,”“analog,” and “composition of matter” stand equally well for thedisclosed chemical entities described herein, including all enantiomericforms, diastereomeric forms, salts, and the like, and the terms“compound,” “analog,” and “composition of matter” are usedinterchangeably throughout the present specification.

The present disclosure addresses several unmet medical needs, interalia;

-   1) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder, disease, malady, or    condition wherein angiogenesis is elevated;-   2) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder, disease, malady, or    condition; and-   3) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby providing a method    for regulating angiogenesis in a disorder, disease, malady, or    condition wherein angiogenesis is decreased.

These and other unmet medical needs are resolved by the human proteintyrosine phosphatase beta (HPTP-β) inhibitors of the present disclosure,that are capable of regulating angiogenesis and thereby serving as amethod for treating elevated or diminished angiogenesis in humans or intreating diseases that are caused by insufficient regulation of humanprotein tyrosine phosphatase beta (HPTP-β).

The compounds disclosed herein include all pharmaceutically acceptablesalt forms, for example, salts of both basic groups, inter alia, amines,as well as salts of acidic groups, inter alia, sulfamic acids, andcarboxylic acids. The following are non-limiting examples of anions thatcan form salts with basic groups: chloride, bromide, iodide, sulfate,bisulfate, carbonate, bicarbonate, phosphate, formate, acetate,propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate,succinate, tartrate, fumarate, citrate, and the like. The following arenon-limiting examples of cations that can form salts of acidic groups:sodium, lithium, potassium, calcium, magnesium, bismuth, and the like.

The compounds of the present disclosure have Formula (I):

wherein the carbon atom having the amino unit has the (S)stereochemistry as indicated in the formula.

R is a substituted or unsubstituted thiazolyl unit having the formula:

R⁴,R⁵, and R⁶ are substituent groups that can be independently chosenfrom a wide variety of inorganic (hydrogen, hydroxyl, amino, halogen orthe like) or organic substituent units, such as alkyls, cycloalkyls,heterocyclic, heteroaryls, and the like, wherein such substituent unitscan optionally have from 1 to 12 carbon atoms, or 1 to 10 carbon atoms,or 1 to six carbon atoms.

One example of compounds of Formula (I), R units relates to thiazol-2-ylunits having the formula:

wherein R⁴ and R⁵ are each independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₆ linear, branched, or cyclicalkyl;

iii) substituted or unsubstituted phenyl;

iv) substituted or unsubstituted heteroaryl; or

R⁴ and R⁵ can be taken together to form a saturated or unsaturated ringhaving from 5 to 7 atoms.

One example of compounds of Formula (I) includes R units having theformula:

wherein R⁵ is hydrogen and R⁴ is a unit chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), tert-butyl (C₄), n-pentyl (C₅), 1-methylbutyl (C₅),2-methylbutyl (C₅), 3-methylbutyl (C₅), cyclopropyl (C₅), n-hexyl (C₆),4-methylpentyl (C₆), and cyclohexyl (C₆).

Another example of compounds of Formula (I), R units include to unitswherein R⁴ is a unit chosen from methyl (C₁), ethyl (C₂), n-propyl (C₃),iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), andtert-butyl (C₄); and R⁵ is a unit chosen from methyl (C₁) or ethyl (C₂).Non-limiting examples of this aspect of R includes4,5-dimethylthiazol-2-yl, 4-ethyl-5-methylthiazol-2-yl,4-methyl-5-ethylthiazol-2-yl, and 4,5-diethylthiazol-2-yl.

A further example of compounds of Formula (I), R units include unitswherein R⁵ is hydrogen and R⁴ is a substituted alkyl unit, saidsubstitutions chosen from:

i) halogen: —F, —Cl, —Br, and —I;

ii) —N(R¹¹)₂; and

iii) —OR¹¹;

wherein each R¹¹ is independently hydrogen or C₁-C₄ linear or branchedalkyl.

Non-limiting examples of units that can be a substitute for hydrogen onR units include —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂Cl, —CH₂OH,—CH₂OCH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, andCH₂NH(CH₂CH₃).

Other non-limiting examples of units that comprise R units include2,2-difluorocyclopropyl, 2-methoxycyclohexyl, and 4-chlorocyclohexyl.

A yet further example of compounds of Formula (I), R units include unitswherein R⁵ is hydrogen and R⁴ is phenyl or substituted phenyl, whereinnon-limiting examples of R⁴ units include phenyl, 3,4-dimethylphenyl,4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl,4-(trifluoromethyl)phenyl, 4-methoxyphenyl, 4-(difluoromethoxy)phenyl,4-(trifluoro-methoxy)phenyl, 3-chloropheny, 4-chlorophenyl, and3,4-dichlorophenyl, which when incorporated into the definition of Raffords the following R units 4-phenylthiazol-2-yl,3,4-dimethylphenylthiazol-2-yl, 4-tert-butylphenylthiazol-2-yl,4-cyclopropylphenylthiazol-2-yl, 4-diethylaminophenylthiazol -2-yl,4-(trifluoromethyl)phenylthiazol-2-yl, 4-methoxyphenylthiazol-2-yl,4-(difluoromethoxy)phenylthiazol-2-yl,4-(trifluoromethoxy)phenylthiazol-2-yl, 3-chloropheny,4-chlorophenylthiazol-2-yl, and 3,4-dichlorophenylthiazol-2-yl.

A still further example of compounds of Formula (I) includes R unitswherein R⁴ is chosen from hydrogen, methyl, ethyl, n-propyl, andiso-propyl and R⁵ is phenyl or substituted phenyl. A non-limitingexample of a R unit according to the fifth aspect of the first categoryof R units includes 4-methyl-5-phenylthiazol-2-yl and4-ethyl-5-phenylthiazol-2-yl.

Another further example of compounds of Formula (I) includes R unitswherein R⁵ is hydrogen and R⁴ is a substituted or unsubstitutedheteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.

Further non-limiting example of compounds of Formula (I) includes Runits wherein R⁴ is substituted or unsubstituted thiophene-2-yl, forexample thiophene-2-yl, 5-chlorothiophene-2-yl, and5-methylthiophene-2-yl.

A still further example of compounds of Formula (I) includes R unitswherein R⁴ is substituted or unsubstituted thiophene-3-yl, for examplethiophene-3-yl, 5-chlorothiophene-3-yl, and 5-methylthiophene-3-yl.

Another example of compounds of Formula (I) includes R units wherein R⁴and R⁵ are taken together to form a saturated or unsaturated ring havingfrom 5 to 7 atoms. Non-limiting examples of the sixth aspect of thefirst category of R units include5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl and4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl.

Further examples of compounds of Formula (I) include R units that arethiazol-4-yl units having the formula:

wherein R⁶ is a unit chosen from:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₆ linear, branched, or        cyclic alkyl;    -   iii) substituted or unsubstituted phenyl rings having from 5 to        10 ring atoms; or    -   iv) substituted or unsubstituted heteroaryl having from 5 to 10        ring atoms.

An example of compounds of Formula (I) includes R units wherein R⁶ ishydrogen.

A further example of compounds of Formula (I) includes R units whereinR⁶ is a unit chosen from methyl (C₁), ethyl (C₂), n-propyl (C₃),iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), andtert-butyl (C₄). Non-limiting examples of this aspect of R includes2-methylthiazol-4-yl, 2-ethylthiazol-4-yl, 2-(n-propyl)thiazol-4-yl, and2-(iso-propyl)thiazol-4-yl.

A still further example of compounds of Formula (I) includes R unitswherein R⁶ is substituted or unsubstituted phenyl, non-limiting examplesof which include phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, and4-methoxyphenyl.

Yet further example of compounds of Formula (I) includes R units whereinR⁶ is substituted or unsubstituted heteroaryl, non-limiting examples ofwhich include thiophene-2-yl, thiophene-3-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl,2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, and 3-methyl-1,2,4-oxadiazol-5-yl.

A further example of compounds of Formula (I) includes R units whereinR⁶ is a unit having the formula:

wherein R⁷ is C₁-C₄ substituted or unsubstituted alkyl and substitutedor unsubstituted phenyl, non-limiting examples of R⁶ include4-chlorobenzenesulfonylmethyl and tert-butylsulfonylmethyl.

A further example of compounds of Formula (I) includes R units whereinR⁶ is a unit chosen from substituted or unsubstituted pyridinyl,pyrazinyl, and pyrimidinyl, non-limiting examples of which includepyrazin-2-yl and (2-methyl)pyridin-5-yl.

R¹ Units

One example of R¹ units includes compounds wherein R¹ is hydrogen. Thecompounds of the present disclosure wherein R¹ is equal to hydrogen havethe formula:

and the compounds of this category therefore do not comprise a secondchiral center.

Another example of compounds of Formula (I) includes R¹ units having asecond chiral center and, for example, having the formulae:

and the indicated stereochemistry. The disclosed compounds can be singlediastereomers or mixtures thereof and can be obtained by the formulatorin any of the following ways:

-   -   i) as a mixture of the (S),(S) and (S),(R) diastereomers and        used as a mixture for regulation of angiogenesis;    -   ii) as a mixture of the (S),(S) and (S),(R) diastereomers that        are then subsequently separated into the single diastereomers        before being used for regulation of angiogenesis; or    -   iii) directly prepared as the individual (S),(S) or (S),(R)        diastereomer, the method further described herein below.

One example of compounds according to Formula (I) includes R units thatare benzyl, non-limiting examples of which include4-{(S)-2-[(S)-2-(tert-butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid,4-{(S)-2-(S)-2-(tert-butoxycarbonyl)-3-phenylpropaneamido-2-(2-phenylthiazole-4-yl)}phenylsulfamicacid,4-{(S)-2-(4-ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]-ethyl}phenylsulfamicacid, and4-{(S)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropan-amido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid, as well as other compounds described herein below.

Another example of compounds according to Formula (I) includes R¹ unitsthat are substituted benzyl, non-limiting examples of which include4-{(S)-2-[(S)-2-(tert-butoxycarbonyl)-3-(4-hydroxyphenyl)propanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid;4-{(S)-2-(S)-2-(tert-butoxycarbonyl)-3-(4-chlorophenyl)propaneamido-2-(2-phenylthiazole-4-yl)}phenylsulfamicacid, and4-{(S)-2-(4-ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-(4-methylphenyl)propanamido]-ethyl}phenylsulfamicacid.

A further example of compounds according to Formula (I) includes R¹units that are phenyl, non-limiting examples of which include4-{(S)-2-[(S)-2-(tert-butoxycarbonyl)-2-phenylethanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid,4-{(S)-2-(S)-2-(tert-butoxycarbonyl)-2-phenylethaneamido-2-(2-phenylthiazole-4-yl)}phenylsulfamicacid, and4-{(S)-2-(4-ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-2-phenylethaneamido]-ethyl}phenylsulfamicacid.

A yet further example of compounds according to Formula (I) includes R¹units that are C₁-C₄ linear or branched alkyl non-limiting examples ofwhich include4-{(S)-2-(4-ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanamido]-ethyl}phenylsulfamicacid,4-{(S)-2-[(S)-2-(tert-butoxycarbonyl)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid, and4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentan-amido]ethyl}phenylsulfamicacid, as well as other compounds described herein below.

R² is a unit chosen from:

i) C₁-C₆ linear or branched alkyl; or

ii) C₁-C₆ linear or branched alkoxy.

One example of R² includes C₁-C₆ linear or branched alkoxy units havingthe formula:—OR⁸wherein R⁸ is a C₁-C₆ linear or branched alkyl unit chosen from methyl(C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), n-pentyl (C₅), orn-hexyl (C₆).

Another example of compounds according to Formula (I) includes R² unitsthat are C₁-C₆ linear or branched alkyl chosen from methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), tert-butyl (C₄), n-pentyl (C₅), or n-hexyl (C₆).

R³ is hydrogen or C₁-C₄ linear or branched alkyl.

One example of R³ includes compounds wherein R³ is hydrogen.

Another example of R³ includes compounds wherein R³ is methyl.

A further example of R³ includes compounds wherein R³ is chosen fromethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl(C₄), iso-butyl (C₄), and tert-butyl (C₄).

The compounds of Formula (I) can be organized into several categoriesfor the strictly non-limiting purpose of describing alternatives forsynthetic strategies for the preparation of subgenera of compoundswithin the scope of Formula (I) that are not expressly exemplifiedherein. This mental organization into categories does not imply anythingwith respect to increased or decreased biological efficacy with respectto any of the compounds or compositions of matter described herein.

The first aspect of Category I of the present disclosure relates tocompounds having the formula:

wherein R is a substituted or unsubstituted thiazol-2-yl unit andnon-limiting examples of R and R¹ and the stereochemistry at R¹ arefurther described in Table I. TABLE I No. R R¹ 1 thiazol-2-yl (S)-benzyl2 4-methylthiazol-2-yl (S)-benzyl 3 4-ethylthiazol-2-yl (S)-benzyl 44-propylthiazol-2-yl (S)-benzyl 5 4-iso-propylthiazol-2-yl (S)-benzyl 64-cyclopropylthiazol-2-yl (S)-benzyl 7 4-butylthiazol-2-yl (S)-benzyl 84-tert-butylthiazol-2-yl (S)-benzyl 9 4-cyclohexylthiazol-2-yl(S)-benzyl 10 4-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl 114-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl 124-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl 134-(methoxymethyl)thiazol-2-yl (S)-benzyl 14 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl 15 4,5-dimethylthiazol-2-yl (S)-benzyl 164-methyl-5-ethylthiazol-2-yl (S)-benzyl 17 4-phenylthiazol-2-yl(S)-benzyl 18 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl 194-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl 204-methyl-5-phenylthiazol-2-yl (S)-benzyl 214-(thiophene-2-yl)thiazol-2-yl (S)-benzyl 224-(thiophene-3-yl)thiazol-2-yl (S)-benzyl 234-(5-chlorothiophene-2-yl)thiazol-2-yl (S)-benzyl 245,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl 254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds encompassed within the first aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in Scheme Iand described in Example 1 herein below.

EXAMPLE 14-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (5)

Preparation of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acidtert-butyl ester (1): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid andN-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwiseiso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at0° C. for 20 minutes after which NH₃ (g) is passed through the reactionmixture for 30 minutes at 0° C. The reaction mixture is concentrated andthe residue dissolved in EtOAc, washed successively with 5% citric acid,water, 5% NaHCO₃, water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to a residue that is triturated with a mixture ofEtOAc/petroleum ether to provide 2.2 g (74%) of the desired product as awhite solid.

Preparation of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]carbamic acidtert-butyl ester (2): To a solution of[1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester,1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent(0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours andconcentrated to a residue which is purified over silica to provide 0.350g (83%) of the desired product. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H),8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70 (d,J=7.2 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s, 9H).

Preparation of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine(3): A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamicacid tert-butyl ester, 2, (0.245 g, 0.753 mmol), 1-bromo-2-butanone(0.125 g, 0.828 mmol) in CH₃CN (5 mL) is refluxed 3 hours. The reactionmixture is cooled to room temperature and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration. Thesolid is dried under vacuum to afford 0.242 g (90% yield) of the desiredproduct. ESI+MS 278 (M+1).

Preparation of{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester (4): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.393 g, 1.1 μmol), (S)-(2-tert-butoxycarbonylamino)-3-phenylpropionic acid (0.220 g, 0.828 mmol) and 1-hydroxybenzotriazole(HOBt) (0.127 g, 0.828 mmol) in DMF (10 mL) at 0° C., is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.159 g, 0.828mmol) followed by diisopropylamine (0.204 g, 1.58 mmol). The mixture isstirred at 0° C. for 30 minutes then at room temperature overnight. Thereaction mixture is diluted with water and extracted with EtOAc. Thecombined organic phase is washed with 1 N aqueous HCl, 5% aqueousNaHCO₃, water and brine, and dried over Na₂SO₄. The solvent is removedin vacuo to afford 0.345 g of the desired product which is used withoutfurther purification. LC/MS ESI+525 (M+1).

Preparation of4-{(S)-2-[(S)-2-(tert-butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (5):{1-[1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester, 4, (0.345 g) is dissolved in MeOH (4mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture isstirred under a hydrogen atmosphere 2 hours. The reaction mixture isfiltered through a bed of CELITE™ and the solvent is removed underreduced pressure. The crude product is dissolved in pyridine (12 mL) andtreated with SO₃-pyridine (0.314 g). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH (50 mL) isadded. The mixture is then concentrated and the resulting residue ispurified by reverse phase chromatography to afford 0.222 g of thedesired product as the ammonium salt. ¹H(CD₃OD): δ 7.50-6.72 (m, 10H),5.44-5.42 (d, 1H, J=6.0 Hz), 4.34 (s, 1H), 3.34-2.79 (m, 4H), 2.83-2.76(q, 2H, J=7.2 Hz), 1.40 (s, 9H), 1.31 (t, 3H, J=7.5 Hz).

The final compounds of the present disclosure can also be isolated asthe free acid. A non-limiting example of this procedure is describedherein below in Example 4.

The following are non-limiting examples of compounds encompassed withinthe first aspect of Category I of the present disclosure.

4-{(S)-2-[(R)-2-(tert-butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.22-7.02 (m, 10H), 5.39 (s, 1H), 4.34 (s, 1H),3.24-2.68 (m, 6H), 1.37 (s, 9H), 1.30 (t, 3H, J=7.5 Hz).

{1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methylcarbamic acid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 8.36 (d,J=8.1 Hz, 1H), 7.04-7.22 (m, 9H), 5.45 (s, 1H), 3.01-3.26 (m, 2H),2.60-2.88 (m, 4H), 2.33 (s, 3H), 1.30 (s, 9H).

{1-[1-(5-Phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methylcarbamic acid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 8.20 (d,J=8.1 Hz, 1H), 7.96-7.99 (m, 2H), 7.48-7.52 (m, 3H), 7.00-7.23 (m, 7H),6.89 (s, 1H), 5.28 (q, J=7.5 Hz, 1H), 4.33 (t, J=6.6 Hz, 1H), 3.09-3.26(m, 2H), 3.34 (dd, J=13.2 and 8.4 Hz, 1H), 2.82 (dd, J=13.2 and 8.4 Hz,1H), 1.38 (s, 9H).

The second aspect of Category I of the present disclosure relates tocompounds having the formula:

wherein R is substituted or unsubstituted thiazol-4-yl unit andnon-limiting examples of R and R¹ and the stereochemistry at R¹ arefurther described in Table II. TABLE II No. R R¹ 26 thiazol-4-yl(S)-benzyl 27 2-methylthiazol-4-yl (S)-benzyl 28 2-ethylthiazol-4-yl(S)-benzyl 29 2-propylthiazol-4-yl (S)-benzyl 302-iso-propylthiazol-4-yl (S)-benzyl 31 2-cyclopropylthiazol-4-yl(S)-benzyl 32 2-butylthiazol-4-yl (S)-benzyl 33 2-tert-butylthiazol-4-yl(S)-benzyl 34 2-cyclohexylthiazol-4-yl (S)-benzyl 352-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl 362-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl 372-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl 382-phenylthiazol-4-yl (S)-benzyl 39 2-(4-chlorophenyl)thiazol-4-yl(S)-benzyl 40 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl 412-(thiophene-2-yl)thiazol-4-yl (S)-benzyl 422-(thiophene-3-yl)thiazol-4-yl (S)-benzyl 432-(3-chlorothiophene-2-yl)thiazol-4-yl (S)-benzyl 442-(3-methylthiophene-2-yl)thiazol-4-yl (S)-benzyl 452-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl 462-(furan-2-yl)thiazol-4-yl (S)-benzyl 47 2-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl 48 2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl 492-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl 502-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl

The compounds encompassed within the second aspect of Category I of thepresent disclosure can be prepared by the procedure outlined in SchemeII and described in Example 2 herein below.

EXAMPLE 24-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido-2-(2-phenylthiazol-4-yl)}phenylsulfamicacid (9)

Preparation of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamicacid tert-butyl ester (6): To a 0° C. solution of2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g,4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). Thereaction mixture is stirred at 0° C. for 20 minutes and filtered. Thefiltrate is treated with an ether solution of diazomethane (˜16 mmol) at0° C. The reaction mixture is stirred at room temperature for 3 hoursthen concentrated in vacuo. The resulting residue is dissolved in EtOAcand washed successively with water and brine, dried (Na₂SO₄), filteredand concentrated. The residue is purified over silica (hexane/EtOAc 2:1)to afford 1.1 g (82% yield) of the desired product as a slightly yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd,J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).

Preparation of (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate (7): To a 0° C.solution of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acidtert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is addeddropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture isstirred at 0° C. for 1.5 hours then the reaction is quenched at 0° C.with sat. Na₂CO₃. The mixture is extracted with EtOAc (3×25 mL) and thecombined organic extracts are washed with brine, dried (Na₂SO₄),filtered and concentrated to obtain 0.400 g of the product which is usedin the next step without further purification. ¹H NMR (300 MHz, CDCl₃) δ8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H),4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).

Preparation of tert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate(8): A mixture of thiobenzamide (0.117 g, 0.85 mmol) and (S)-tert-butyl4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (0.300 g, 0.77mmol) in CH₃CN (4 mL) is refluxed 2 hours. The reaction mixture iscooled to room temperature and diethyl ether is added to precipitate theintermediate 2-(nitrophenyl)-(S)-1-(4-phenylthiazol-2-yl)ethylaminewhich is isolated by filtration as the hydrobromide salt. Thehydrobromide salt is dissolved in DMF (3 mL) together withdiisoproylethylamine (0.42 mL, 2.31 mmol), 1-hydroxybenzotriazole (0.118g, 0.79 mmol) and (S)-(2-tert-butoxycarbonylamino)-3-phenylpropionicacid (0.212 g, 0.80 mmol). The mixture is stirred at 0° C. for 30minutes then at room temperature overnight. The reaction mixture isdiluted with water and extracted with EtOAc. The combined organic phaseis washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, water and brine, anddried over Na₂SO₄. The solvent is removed in vacuo to afford 0.395 g(90% yield) of the desired product which is used without furtherpurification. LC/MS ESI+573 (M+1).

Preparation of4-{(S)-2-(S)-2-(tert-butoxycarbonyl)-3-phenylpropaneamido-2-(2-phenylthiazole-4-yl)}phenylsulfamicacid (9): tert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,8, (0.360 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 12 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.296 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (10 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.050 g of the desired product as the ammoniumsalt. ¹H NMR (300 MHz, MeOH-d₄) δ 8.20 (d, J=8.1 Hz, 1H), 7.96-7.99 (m,2H), 7.48-7.52 (m, 3H), 7.00-7.23 (m, 7H), 6.89 (s, 1H), 5.28 (q, J=7.5Hz, 1H), 4.33 (t, J=6.6Hz, 1H), 3.09-3.26 (m, 2H), 3.34 (dd, J=13.2 and8.4 Hz, 1H), 2.82 (dd, J=13.2 and 8.4 Hz, 1H), 1.38 (s, 9H).

The first aspect of Category II of the present disclosure relates tocompounds having the formula:

wherein R is a substituted or unsubstituted thiazol-2-yl unit andnon-limiting examples of R and R¹ and the stereochemistry at R¹ arefurther described in Table III. TABLE III No. R R¹ 51 thiazol-2-yl(S)-benzyl 52 4-methylthiazol-2-yl (S)-benzyl 53 4-ethylthiazol-2-yl(S)-benzyl 54 4-propylthiazol-2-yl (S)-benzyl 554-iso-propylthiazol-2-yl (S)-benzyl 56 4-cyclopropylthiazol-2-yl(S)-benzyl 57 4-butylthiazol-2-yl (S)-benzyl 58 4-tert-butylthiazol-2-yl(S)-benzyl 59 4-cyclohexylthiazol-2-yl (S)-benzyl 604-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl 614-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl 624-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl 634-(methoxymethyl)thiazol-2-yl (S)-benzyl 64 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl 65 4,5-dimethylthiazol-2-yl (S)-benzyl 664-methyl-5-ethylthiazol-2-yl (S)-benzyl 67 4-phenylthiazol-2-yl(S)-benzyl 68 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl 694-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl 704-methyl-5-phenylthiazol-2-yl (S)-benzyl 714-(thiophene-2-yl)thiazol-2-yl (S)-benzyl 724-(thiophene-3-yl)thiazol-2-yl (S)-benzyl 734-(5-chlorothiophene-2-yl)thiazol-2-yl (S)-benzyl 745,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl 754,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds encompassed within the first aspect of Category II of thepresent disclosure can be prepared by the procedure outlined in SchemeIII and described in Example 3 herein below.

EXAMPLE 34-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (11)

Preparation ofmethyl-(S)-1-[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl-amino]-1-oxo-3-phenylpropan-2-ylcarbamate(10): tert-butyl(S)-1-(S)-2-(4-nitro-phenyl)-1-(2-phenylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,8, (0.460 mg, 0.881 mmol) is dissolved in a solution of 4M hydrogenchloride in 1,4-dioxane (4 mL). The reaction mixture is stirred 1 hour,and the solvent is removed under reduced pressure. The resulting crudeamine is dissolved in CHCl₃ (8 mL) and pyridine (1 mL) is added. Thetemperature is cooled to 0° C. and methyl chloroformate (0.083 g, 0.881mmol) is added dropwise. The reaction mixture is allowed to warm to roomtemperature and stirred for 2 days. Water is added, the solution stirredfor 15 minutes and then extracted several times with CHCl₃. The combinedorganic layers are washed with 1N HCl, 5% NaHCO₃, and brine, dried overNa₂SO₄, and filtered. The solvent is removed in vacuo to afford 0.297 gof the desired product.

Preparation of4-{(S)-2-(4-ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid (11):Methyl-(S)-1-[(S)-1-(4-ethyl-thiazol-2-yl)-2-(4-nitrophenyl)ethyl-amino]-1-oxo-3-phenylpropan-2-ylcarbamate,10, (0.297 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 4 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.196 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (25 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography silica to afford 0.172 g of the desired product as theammonium salt. ¹H(CD₃OD): δ 7.26-7.00 (m, 10H), 5.39 (t, 1H, J=5.7 Hz),4.38 (t, 1H, J=5.7 Hz), 3.62 (s, 3H), 3.34-2.75 (m, 6H), 1.30 (t, 3H,J=7.5 Hz).

The following are non-limiting examples of the first aspect of CategoryII of the present disclosure.

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(thiazol-2-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.78-7.75 (m, 1H), 7.51-7.47 (m, 1H), 7.30-7.02 (m,9H), 5.49-5.43 (m, 1H), 4.39 (t, 1H, J=8.1 Hz), 3.56 (s, 3H), 3.51-2.71(m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-methylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.52-8.49 (m, 1H), 7.20-6.99 (m, 10H),5.37 (bs, 1H), 4.36 (bs, 1H), 3.62-3.48 (m, 3H), 3.32-3.22 (m, 1H),3.11-3.01 (m, 2H), 2.80-2.72 (m, 1H), 2.42 (s, 3H).

4-{(S)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]-2-(4-propylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.51-8.49 (m, 1H), 7.22-6.99 (m, 10H),5.39 (t, J=6.0 Hz, 1H), 4.38 (dd, J=14.4, 9.0 Hz, 1H), 3.62 (s, 2H),3.59-3.48 (m, 1H), 3.27 (dd, J=13.5, 6.3 Hz, 1H), 3.12-3.02 (m, 2H),2.81-2.71 (m, 3H), 1.81-1.68 (m, 2H), 0.985 (t, J=7.5 Hz, 3H).

4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.23-7.19 (m, 5H), 7.10-6.98 (m, 5H),5.42-5.38 (m, 1H), 4.37 (dd, J=8.4, 5.4 Hz, 1H), 3.61 (s, 2H), 3.48 (bs,1H), 3.32-3.25 (m, 1H), 3.13-3.07 (m, 2H), 2.77 (dd, J=13.5, 9.3 Hz,1H), 1.36 (s, 9H).

4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.13-6.91 (m, 10H), 6.81 (s, 1H), 5.23 (t, 1H, J=7.8Hz), 4.24 (t, 1H, J=8.4 Hz), 3.50 (s, 3H), 3.12-2.66 (m, 4H), 1.94 (t,1H, J=5.1 Hz), 0.84-0.73 (m, 4H).

4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.21-6.97 (m, 10H), 5.45-5.25 (m, 1H),5.42-5.36 (m, 1H), 5.10-5.02 (m, 1H), 4.03-4.35 (m, 1H), 3.63 (s, 2H),3.60-3.49 (m, 1H), 3.12-3.06 (m, 1H), 2.95 (dd, J=14.1, 9.9 Hz, 1H),2.82-2.72 (m, 2H), 2.07-1.77 (m, 3H), 1.56-1.31 (m, 10H).

4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.45 (d, J=7.8 Hz, 1H), 7.22-7.03 (m,9H), 5.28 (t, J=7.2 Hz, 1H), 4.36 (t, J=7.8 Hz, 1H), 3.62 (s, 2H),3.52-3.46 (m, 1H), 3.22 (dd, J=14.1, 6.3 Hz, 1H), 3.07-2.99 (m, 2H),2.77 (dd, J=13.5, 8.4 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H).

4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.45 (d, J=8.1 Hz, 1H), 7.36-7.00 (m,9H), 5.31 (bs, 1H), 4.37 (bs, 1H), 3.62-3.46 (m, 3H), 3.28-2.64 (m, 6H),2.34 (d, J=5.4 Hz, 3H), 1.37-1.20 (m, 3H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.40 (d, J=11.1 Hz, 1H), 7.30-7.15 (m,5H), 7.12-7.00 (m, 5H), 5.41 (dd, J=8.4, 5.1 Hz, 1H), 4.42-4.36 (m, 1H),3.77-3.52 (m, 5H), 3.33-3.23 (m, 1H), 3.15-3.02 (m, 2H), 2.97-2.91 (m,1H), 2.82-2.70 (m, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido)-2-[4-(3,3,3-trifluoropropyl)thiazol-2-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.23-7.03 (m, 10H), 5.46-5.34 (m, 1H),4.54-4.44 (m, 1H), 3.63 (s, 2H), 3.62-3.35 (m, 1H), 3.34-3.24 (m, 1H),3.17-2.99 (m, 4H), 2.82-2.74 (m, 1H), 2.69-2.56 (m, 2H).

4-{(S)-2-[4-(2,2-Difluorocyclopropyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.28-7.00 (m, 10H), 5.42-5.37 (m, 1H),4.41-4.38 (m, 1H), 3.60 (s, 2H), 3.61-3.52 (m, 1H), 3.35-3.23 (m, 1H),3.04-2.91 (m, 2H), 2.78-2.68 (m, 1H), 1.99-1.90 (m, 2H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(methoxy-methyl)thiazol-2-yl]ethyl}phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 8.55(d, J=6.6 Hz, 1H), 7.31 (s, 1H), 7.21-7.05 (m, 9H), 5.41 (bs, 1H), 4.53(s, 2H), 4.37 (bs, 1H), 3.62 (s, 2H), 3.59-3.46 (m, 1H), 3.41 (s, 3H),3.28-3.22 (m, 1H), 3.13-3.00 (m, 3H), 2.80-2.72 (m, 1H).

4-{(S)-2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.25 (s, 1H), 7.20-7.07 (m, 10H), 5.40(dd, J=7.5 Hz, 1H), 4.45-4.36 (m, 3H), 3.63 (s, 2H), 3.60-3.51 (m, 1H),3.34-3.27 (m, 1H), 3.17-3.00 (m, 2H), 2.79 (dd, J=13.5, 8.4 Hz, 1H),1.42 (t, J=7.5 Hz, 3H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(5-phenylthiazol-2-yl))ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.63 (d, J=8.1 Hz, 1H), 7.96 (s, 1H),7.59 (d, J=7.8 Hz, 2H), 7.47-7.36 (m, 3H), 7.19-7.10 (m, 10H), 5.42-5.40(m, 1H), 4.41 (t, J=7.2, 1H), 3.65-3.50 (m, 3H), 3.16-2.77 (m, 4H).

4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.50-7.38 (m, 4H), 7.21-7.11 (m, 10H),5.45-5.35 (m, 1H), 5.42-4.37 (m, 1H), 3.63-3.50 (m, 3H), 3.34-3.29 (m,3H), 3.15-3.03 (m, 2H), 2.84-2.74 (m, 3H), 1.31-1.21 (m, 3H).

4-{(S)-2-[4-(3,4-dimethylphenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.60 (d, J=8.1 Hz, 1H), 7.73 (s, 1H),7.65 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.21-7.11 (m, 10H), 5.47 (d, J=7.2Hz, 1H), 4.44-4.38 (m, 1H), 3.63 (s, 2H), 3.62-3.51 (m, 1H), 3.40-3.32(m, 1H), 3.20-3.05 (m, 2H), 2.84-2.77 (m, 1H), 2.35 (s, 3H), 2.32 (s,3H).

4-{(S)-2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.65 (d, J=8.4 Hz, 1H), 7.95-7.91 (m,2H), 7.70 (s, 1H), 7.46-7.41 (m, 2H), 7.19-7.10 (m, 9H), 5.50-5.45 (m,1H), 4.41 (t, J=6.6 Hz, 1H), 3.63 (s, 2H), 3.62-3.51 (m, 1H), 3.41-3.33(m, 1H), 3.20-3.04 (m, 2H), 2.81 (dd, J=13.8, 9.0 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-phenylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.94-7.92 (d, 2H, J=7.3 Hz), 7.65 (s, 1H), 7.45-7.31(m, 3H), 7.22-7.10 (m, 9H), 5.46 (t, 1H, J=6.8 Hz), 4.39 (m, 1H), 3.62(s, 3H), 3.36-2.79 (m, 6H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.63 (d, J=8.1 Hz, 1H), 7.52-7.51 (m,2H), 7.39 (dd, J=5.1, 1.2 Hz, 1H), 7.20-7.08 (m, 10H), 5.50-5.40 (m,1H), 4.39 (t, J=8.1 Hz, 1H), 3.63 (s, 2H), 3.50 (bs, 1H), 3.39-3.32 (m,1H), 3.18-3.04 (m, 2H), 2.80 (dd, J=13.5, 8.7 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.60 (d, J=7.8 Hz, 1H), 7.83 (d, J=1.5Hz, 1H), 7.56-7.46 (m, 3H), 7.14 (d, J=25.2 Hz, 10H), 5.46-5.43 (m, 1H),4.40-4.38 (m, 1H), 3.62 (s, 3H), 3.55-3.45 (m, 1H), 3.19-3.04 (m, 4H),2.84-2.75 (m, 1H).

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropion-amido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.45-8.56 (m, 1H), 7.01-7.25 (m, 9H),7.03 (s, 1H), 5.40-5.5.0 (m, 1H), 3.48-3.65 (m, 3H), 3.36 (dd, J=14.4and 6.0 Hz, 1H), 3.23 (dd, J=14.4 and 6.0 Hz, 1H), 2.95-3.10 (m, 1H),2.75-2.86 (m, 3H), 2.57-2.64 (m, 3H), 1.30 (t, J=7.5 Hz, 3H).

4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD):δ 8.46 (bs, 1H), 7.16-7.05 (m, 9H), 5.31 (bs, 1H), 4.35 (bs, 1H), 3.61(s, 2H), 3.52-3.43 (m, 1H), 3.28-3.18 (m, 1H), 3.10-2.98 (m, 2H),2.92-2.74 (m, 4H), 2.58-2.44 (m, 2H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.21-7.08 (m, 9H), 5.45-5.25 (m, 1H),4.45-4.30 (m, 1H), 3.63 (s, 2H), 3.64-3.34 (m, 1H), 3.33-3.20 (m, 1H),3.09-3.02 (m, 2H), 2.75 (bs, 5H), 1.90 (bs, 4H).

4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.63 (d, J=8.7 Hz, 1H), 7.55 (s, 1H),7.39-7.31 (m, 1H), 7.23-7.10 (m, 9H), 7.00-6.97 (m, 1H), 5.43-5.40 (m,1H), 5.39 (t, J=14.7 Hz, 1H), 3.63 (s, 2H), 3.60-3.51 (m, 1H), 3.34-3.27(m, 1H), 3.17-3.03 (m, 2H), 2.80 (dd, J=14.1, 8.4 Hz, 1H).

A further iteration of the first aspect of Category II relates tocompounds wherein R² comprises —OCH₂CH₃ (ethoxy); the following is anon-limiting example thereof.

4-{(S)-2-[(S)-2-(Ethoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.22-7.00 (m, 10H), 5.39 (t, 1H, J=6.0 Hz), 4.37 (t,1H, J=6.1 Hz), 4.08-4.00 (q, 2H, J=7.1 Hz), 3.25-2.74 (m, 6H), 1.30 (t,3H, J=7.5 Hz), 1.20 (t, 3H, J=6.9 Hz).

The second aspect of Category II of the present disclosure relates tocompounds having the formula:

wherein R is a substituted or unsubstituted thiazol-4-yl unit andnon-limiting examples of R and R¹ and the stereochemistry at R¹ arefurther described in Table IV. TABLE IV No. R R¹ 76 thiazol-4-yl(S)-benzyl 77 2-methylthiazol-4-yl (S)-benzyl 78 2-ethylthiazol-4-yl(S)-benzyl 79 2-propylthiazol-4-yl (S)-benzyl 802-iso-propylthiazol-4-yl (S)-benzyl 81 2-cyclopropylthiazol-4-yl(S)-benzyl 82 2-butylthiazol-4-yl (S)-benzyl 83 2-tert-butylthiazol-4-yl(S)-benzyl 84 2-cyclohexylthiazol-4-yl (S)-benzyl 852-(2,2,2-trifluoroethyl)thiazol-4-yl (S)-benzyl 862-(3,3,3-trifluoropropyl)thiazol-4-yl (S)-benzyl 872-(2,2-difluorocyclopropyl)thiazol-4-yl (S)-benzyl 882-phenylthiazol-4-yl (S)-benzyl 89 2-(4-chlorophenyl)thiazol-4-yl(S)-benzyl 90 2-(3,4-dimethylphenyl)thiazol-4-yl (S)-benzyl 912-(thiophene-2-yl)thiazol-4-yl (S)-benzyl 922-(thiophene-3-yl)thiazol-4-yl (S)-benzyl 932-(3-chlorothiophene-2-yl)thiazol-4-yl (S)-benzyl 942-(3-methylthiophene-2-yl)thiazol-4-yl (S)-benzyl 952-(2-methylthiazol-4-yl)thiazol-4-yl (S)-benzyl 962-(furan-2-yl)thiazol-4-yl (S)-benzyl 97 2-(pyrazin-2-yl)thiazol-4-yl(S)-benzyl 98 2-[(2-methyl)pyridin-5-yl]thiazol-4-yl (S)-benzyl 992-(4-chlorobenzenesulfonylmethyl)thiazol-4-yl (S)-benzyl 1002-(tert-butylsulfonylmethyl)thiazol-4-yl (S)-benzyl

The compounds encompassed within the second aspect of Category II of thepresent disclosure can be prepared by the procedure outlined in SchemeIV and described in Example 4 herein below.

EXAMPLE 44-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid (13)

Preparation of methyl(S)-1-[(S)-1-(2-ethylthiazole-4-yl)-2-(4-nitrophenyl)-ethyl]amino-1-oxo-3-phenylpropane-2-ylcarbamate(12): A mixture of propanethioamide (69 mg, 0.78 mmol) and(S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7,(0.300 g, 0.77 mmol) in CH₃CN (4 mL) is refluxed for 2 hours. Thereaction mixture is cooled to room temperature and diethyl ether isadded to precipitate the intermediate2-(nitrophenyl)-(S)-1-(4-ethylthiazol-2-yl)ethylamine which is isolatedby filtration as the hydrobromide salt. The hydrobromide salt isdissolved in DMF (8 mL) together with diisoproylethylamine (0.38 mL,2.13 mmol), 1-hydroxybenzotriazole (107 mg, 0.71 mmol) and(S)-(2-methoxycarbonyl-amino)-3-phenylpropionic acid (175 mg, 0.78mmol). The mixture is stirred at 0° C. for 30 minutes then at roomtemperature overnight. The reaction mixture is diluted with water andextracted with EtOAc. The combined organic phase is washed with 1 Naqueous HCl, 5% aqueous NaHCO₃, water and brine, and dried over Na₂SO₄.The solvent is removed in vacuo to afford 0.300 g (81% yield) of thedesired product which is used without further purification. LC/MS ESI+MS483 (M+1).

Preparation of4-((S)-2-((S)-2-(methoxycarbonyl)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamicacid ammonium salt (13): tert-Butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,12, (0.300 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 18 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(223 mg, 1.40 mmol). The reaction is stirred at room temperature for 5minutes after which a 7% solution of NH₄OH (12 mL) is added. The mixtureis then concentrated and the resulting residue is purified by reversephase chromatography to afford 25 mg of the desired product as theammonium salt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.14-7.24 (m, 6H), 6.97-7.0(m, 4H), 6.62 (s, 1H), 5.10-5.30 (m, 1H), 4.36 (t, J=7.2 Hz, 1H), 3.63(s, 3H), 3.14 (dd, J=13.5 and 6.3 Hz, 1H), 2.93-3.07 (m, 5H), 2.81 (dd,J=13.5 and 6.3 Hz, 1H), 1.39 (t, J=7.8 Hz, 3H).

In another iteration of the process of the present disclosure, compound13, as well as the other analogs which comprise the present disclosure,can be isolated as the free acid by adapting the procedure describedherein below.

EXAMPLE 4a4-((S)-2-((S)-2-(Methoxycarbonyl)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamicacid [Free Acid Form] (13)

Preparation of{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester (12a): A Parr hydrogenation vessel is charged withtert-butyl(S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate,12, (18.05 g, 37.4 mmol, 1.0 eq) and Pd/C (10% Pd on C, 50% wet,Degussa-type E101 NE/W, 2.68 g, 15 wt %) as solids. MeOH (270 mL, 15mL/g) is added to provide a suspension. The vessel is put on a Parrhydrogenation apparatus. The vessel is submitted to a fill/vacuumevacuate process with N₂ (3×20 psi) to inert, followed by the sameprocedure with H₂ (3×40 psi). The vessel is filled with H₂ and thevessel is shaken under 40 psi H₂ for ˜40 hr. The vessel is evacuated andthe atmosphere is purged with N₂ (5×20 psi). An aliquot is filtered andanalyzed by HPLC to insure complete conversion. The suspension isfiltered through a pad of celite to remove the catalyst, and thehomogeneous yellow filtrate is concentrated by rotary evaporation toafford 16.06 g (95% yield) of the desired product as a tan solid, whichis used without further purification.

Preparation of4-((S)-2-((S)-2-(methoxycarbonyl)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamicacid (13): A 100 mL RBF is charged with{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester, 12a, (10.36 g, 22.9 mmol, 1.0 eq) prepared in thestep described herein above. Acetonitrile (50 mL, 5 mL/g) is added andthe yellow suspension is stirred at room temperature. A second 3-necked500 mL RBF is charged with SO₃.pyr (5.13 g, 32.2 mmol, 1.4 eq) andacetonitrile (50 mL 5 mL/g) and the white suspension is stirred at roomtemperature. Both suspensions are gently heated until the reactionsolution containing{1-[2-(S)-(4-(S)-aminophenyl)-1-(2-ethylthiazol-4-yl)ethyl-carbamoyl]-2-phenylethyl}-carbamicacid methyl ester becomes red-orange in color (typically for thisexample about 44° C.). This substrate containing solution is poured inone portion into the stirring suspension of SO₃.pyr at 35° C. Theresulting opaque mixture (39° C.) is stirred vigorously while allowed toslowly cool to room temperature. After stirring for 45 min, the reactionis determined to be complete by HPLC. H₂O (200 mL, 20 mL/g) is added tothe orange suspension to provide a yellow-orange homogeneous solutionhaving a pH of approximately 2.4. Concentrated H₃PO₄ is added slowlyover 12 minutes to lower the pH to approximately 1.4. During this pHadjustment, an off-white precipitate is formed and the solution isstirred at room temperature for 1 hr. The suspension is filtered and thefilter cake is washed with the filtrate. The filter cake is air-dried onthe filter overnight to afford 10.89 g (89% yield) of the desiredproduct as a tan solid.

The following are further non-limiting examples of the second aspect ofCategory II of the present disclosure.

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.15 (d, J=8.4 Hz, 1H), 7.16-7.25 (m,5H), 6.97-7.10 (m, 4H), 6.61 (s, 1H), 5.00-5.24 (m, 1H), 4.36 (t, J=7.2Hz, 1H), 3.64 (s, 2H), 3.11-3.19 (s, 1H), 2.92-3.04 (s, 2H), 2.81 (dd,J=13.5 and 8.1 Hz, 1H), 2.75 (s, 3H).

4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropan-amido]ethyl}phenylsulfamicacid: ¹HNMR (300 MHz, MeOH-d₄) 67.16-7.29 (m, 5H), 7.02-7.12 (m, 4H),6.83 (s, 1H), 5.10-5.35 (m, 1H), 3.52-3.67 (m, 3H), 3.18-3.25 (m, 2H),3.05 (q, J=7.5 Hz, 2H), 2.82-2.95 (m, 2H), 2.65 (s, 3H), 1.39 (t, J=7.5Hz, 3H).

4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropan-amido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.16 (d, 1H, J=8.7 Hz), 7.22-7.13 (m, 3H), 7.07(d, 1H, J=8.4 Hz), 6.96 (d, 1H, J=8.1 Hz), 6.62 (s, 1H), 5.19 (t, 1H,J=7.2 Hz), 4.36 (t, 1H, J=7.8 Hz), 3.63 (s, 3H), 3.08 (1H, A of ABX,J=3.6, 14.5 Hz), 2.99 (1H, B of ABX, J=7.2, 13.8 Hz), 2.85-2.78 (m, 1H),1.41 (d, 6H, J=6.9 Hz).

4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.15-7.02 (m, 5H), 6.96-6.93 (d, 2H, J=8.4 Hz),6.86-6.83 (d, 2H, J=8.3 Hz), 6.39 (s, 1H), 5.01 (t, 1H, J=5.0 Hz), 4.22(t, 1H, J=7.4 Hz), 3.51 (s, 3H), 2.98-2.69 (m, 2H), 2.22-2.21 (m, 1H),1.06-1.02 (m, 2H), 0.92-0.88 (m, 2H).

4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid: ¹H(CD₃OD): δ 7.96-7.93(d, 2H, J=8.6 Hz), 7.83-7.80 (d, 2H, J=8.6 Hz), 7.44-7.34 (m, 5H),7.29-7.27 (d, 2H, J=8.4 Hz), 7.14-7.11 (d, 2H, J=8.4 Hz), 6.97 (s, 1H),5.31 (t, 1H, J=6.8 Hz), 5.22-5.15 (m, 2H), 4.55 (t, 1H, J=7.3 Hz), 3.84(s, 3H), 3.20-2.96 (m, 4H).

4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid: ¹H(CD₃OD): δ7.40-7.30(m, 5H), 7.21-7.10 (m, 4H), 7.02 (s, 1H), 5.37 (t, 1H, J=6.9 Hz),5.01-4.98 (m, 2H), 4.51 (t, 1H, J=7.1 Hz), 3.77 (s, 3H), 3.34-2.91 (m,4H), 1.58 (s, 9H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropionamido]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamic acid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.96-7.99(m, 2H), 7.51-7.56 (m, 3H), 7.13-7.38 (m, 6H), 6.92-6.95 (m, 4H),5.11-5.16 (m, 1H), 4.32-4.35 (m, 1H), 3.51 (s, 3H), 3.39-3.40 (m, 2H),3.09-3.19 (m, 1H), 2.92-3.02 (m, 2H), 2.75 (dd, J=10.5 Hz and 9.9 Hz,1H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.61-7.56 (m, 2H), 7.25-7.01 (m, 10H), 6.75 (s, 1H),5.24-5.21 (q, 1H, J=7.2 Hz), 4.38 (t, 1H, J=7.2 Hz), 3.60 (s, 3H),3.23-3.14 (m, 1H), 3.08-3.00 (m, 2H), 2.87-2.80 (m, 1H).

4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.78-7.76 (d, 1H, J=5.4 Hz), 7.36-7.14 (m, 10H), 7.03(s, 1H), 5.39 (t, 1H, J=6.9 Hz), 4.54 (t, 1H, J=7.3 Hz), 3.80 (s, 3H),3.39-2.98 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.38 (d, 1H, J=5.1 Hz), 7.15-6.93 (m, 10H), 6.73 (s,1H), 5.17 (t, 1H, J=6.9 Hz), 4.31 (t, 1H, J=7.3 Hz), 3.57 (s, 3H),3.18-3.11 (m, 1H), 3.02-2.94 (m, 2H), 2.80-2.73 (m, 1H), 2.46 (s, 3H).

4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 7.54-7.46 (m, 1H), 7.02-6.79 (m, 10H), 6.55-6.51 (m,1H), 6.44-6.41 (m, 1H), 5.02-5.00 (q, 1H, J=6.4 Hz), 4.16-4.14 (q, 1H,J=7.1 Hz), 3.43 (s, 3H), 2.96-2.58 (m, 4H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(2-methylthiazole-4-yl)thiazole-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.27 (d, J=5.4 Hz, 1H), 7.97 (s, 1H),6.99-7.21 (m, 8H), 5.18-5.30 (m, 1H), 4.30-4.39 (m, 1H), 3.64 (s, 3H),3.20 (dd, J=14.1 and 6.6 Hz, 1H), 2.98-3.08 (m, 2H), 2.84 (dd, J=14.1and 6.6 Hz, 1H), 2.78 (s, 3H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-pyrazine-2-yl)thiazole-4-yl}phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 9.34 (s, 1H), 8.65 (s, 2H), 8.34 (d,J=8.1 Hz, 1H), 7.00-5.16 (m. 9H), 5.30 (q, J=7.2 Hz, 1H), 4.41 (t, J=7.2Hz, 1H), 3.65 (s, 3H), 3.23 (dd, J=13.8 and 6.9 Hz, 1H), 2.98-3.13 (m,2H), 2.85 (dd, J=13.8 and 6.9 Hz, 1H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(6-methylpyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H(CD₃OD): δ 8.90 (s, 1H), 8.19-8.13 (m, 1H), 7.39-7.36 (d, 1H,J=8.2 Hz), 7.07-6.88 (m, 9H), 6.79 (s, 1H), 5.17 (t, 1H, J=7.0 Hz), 4.29(t, 1H, J=7.4 Hz), 3.54 (s, 3H), 3.10-2.73 (m, 4H), 2.53 (s, 3H).

Category III of the present disclosure relates to compounds having theformula:

wherein R is a substituted or unsubstituted thiazol-2-yl unit andnon-limiting examples of R and R¹ and the stereochemistry at R¹ arefurther described in Table V. TABLE V No. R R¹ 101 thiazol-2-yl(S)-benzyl 102 4-methylthiazol-2-yl (S)-benzyl 103 4-ethylthiazol-2-yl(S)-benzyl 104 4-propylthiazol-2-yl (S)-benzyl 1054-iso-propylthiazol-2-yl (S)-benzyl 106 4-cyclopropylthiazol-2-yl(S)-benzyl 107 4-butylthiazol-2-yl (S)-benzyl 1084-tert-butylthiazol-2-yl (S)-benzyl 109 4-cyclohexylthiazol-2-yl(S)-benzyl 110 4-(2,2,2-trifluoroethyl)thiazol-2-yl (S)-benzyl 1114-(3,3,3-trifluoropropyl)thiazol-2-yl (S)-benzyl 1124-(2,2-difluorocyclopropyl)thiazol-2-yl (S)-benzyl 1134-(methoxymethyl)thiazol-2-yl (S)-benzyl 114 4-(carboxylic acid ethylester)thiazol-2-yl (S)-benzyl 115 4,5-dimethylthiazol-2-yl (S)-benzyl116 4-methyl-5-ethylthiazol-2-yl (S)-benzyl 117 4-phenylthiazol-2-yl(S)-benzyl 118 4-(4-chlorophenyl)thiazol-2-yl (S)-benzyl 1194-(3,4-dimethylphenyl)thiazol-2-yl (S)-benzyl 1204-methyl-5-phenylthiazol-2-yl (S)-benzyl 1214-(thiophene-2-yl)thiazol-2-yl (S)-benzyl 1224-(thiophene-3-yl)thiazol-2-yl (S)-benzyl 1234-(5-chlorothiophene-2-yl)thiazol-2-yl (S)-benzyl 1245,6-dihydro-4H-cyclopenta[d]thiazol-2-yl (S)-benzyl 1254,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (S)-benzyl

The compounds encompassed within Category III of the present disclosurecan be prepared by the procedure outlined in Scheme V and described inExample 5 herein below.

EXAMPLE 54-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid (15)

Preparation of(S)-2-acetamido-N—[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-3-phenylpropanamide(14): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.343 g, 0.957 mmol), N-acetyl-L-phenylalanine (0.218 g),1-hydroxybenzotriazole (HOBt) (0.161 g), diisopropyl-ethylamine (0.26g), in DMF (10 mL) at 0°, is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.201 g). Themixture is stirred at 0° C. for 30 minutes then at room temperatureovernight. The reaction mixture is diluted with water and extracted withEtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5%aqueous NaHCO₃, water and brine, and dried over Na₂SO₄. The solvent isremoved in vacuo to afford 0.313 g (70% yield) of the desired productwhich is used without further purification. LC/MS ESI+467 (M+1).

Preparation of4-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl)phenylsulfamicacid (15):(S)-2-Acetamido-N—[(S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl]-3-phenylpropanamide,14, (0.313 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C(10% w/w) is added and the mixture is stirred under a hydrogenatmosphere 2 hours. The reaction mixture is filtered through a bed ofCELITE™ and the solvent is removed under reduced pressure. The crudeproduct is dissolved in pyridine (12 mL) and treated with SO₃-pyridine(0.320 g). The reaction is stirred at room temperature for 5 minutesafter which a 7% solution of NH₄OH (30 mL) is added. The mixture is thenconcentrated and the resulting residue is purified by reverse phasechromatography to afford 0.215 g of the desired product as the ammoniumsalt. ¹H(CD₃OD): δ 7.23-6.98 (m, 10H), 5.37 (t, 1H), 4.64 (t, 1H, J=6.3Hz), 3.26-2.74 (m, 6H), 1.91 (s, 3H), 1.29 (t, 3H, J=7.5 Hz).

The following are further non-limiting examples of compounds encompassedwithin Category III of the present disclosure.

4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 7.22-7.17 (m, 5H), 7.06 (dd, J=14.1,8.4 Hz, 4H), 6.97 (d, J=0.9 Hz, 1H), 5.39 (dd, J=8.4, 6.0 Hz, 1H), 4.65(t, J=7.2 Hz, 1H), 3.33-3.26 (m, 1H), 3.13-3.00 (m, 3H), 2.80 (dd,J=13.5, 8.7 Hz, 1H), 1.91 (s, 3H), 1.36 (s, 9H).

4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, CD₃OD): δ 8.58 (d, J=8.1 Hz, 1H), 7.83-7.82 (m,1H), 7.57-7.46 (m, 3H), 7.28-6.93 (m, 11H), 5.54-5.43 (m, 1H), 4.69-4.55(m, 2H), 3.41-3.33 (m, 1H), 3.14-3.06 (3H), 2.86-2.79 (m, 1H), 1.93 (s,3H).

The first aspect of Category IV of the present disclosure relates tocompounds having the formula:

wherein R is a substituted or unsubstituted thiophene-2-yl unit andnon-limiting examples of R and R¹ and the stereochemistry at R¹ arefurther described in Table VI. TABLE VI No. R R¹ 126 thiazol-2-ylhydrogen 127 4-methylthiazol-2-yl hydrogen 128 4-ethylthiazol-2-ylhydrogen 129 4-propylthiazol-2-yl hydrogen 130 4-iso-propylthiazol-2-ylhydrogen 131 4-cyclopropylthiazol-2-yl hydrogen 132 4-butylthiazol-2-ylhydrogen 133 4-tert-butylthiazol-2-yl hydrogen 1344-cyclohexylthiazol-2-yl hydrogen 135 4,5-dimethylthiazol-2-yl hydrogen136 4-methyl-5-ethylthiazol-2-yl hydrogen 137 4-phenylthiazol-2-ylhydrogen 138 thiazol-2-yl (S)-iso-propyl 139 4-methylthiazol-2-yl(S)-iso-propyl 140 4-ethylthiazol-2-yl (S)-iso-propyl 1414-propylthiazol-2-yl (S)-iso-propyl 142 4-iso-propylthiazol-2-yl(S)-iso-propyl 143 4-cyclopropylthiazol-2-yl (S)-iso-propyl 1444-butylthiazol-2-yl (S)-iso-propyl 145 4-tert-butylthiazol-2-yl(S)-iso-propyl 146 4-cyclohexylthiazol-2-yl (S)-iso-propyl 1474,5-dimethylthiazol-2-yl (S)-iso-propyl 148 4-methyl-5-ethylthiazol-2-yl(S)-iso-propyl 149 4-phenylthiazol-2-yl (S)-iso-propyl 1504-(thiophene-2-yl)thiazol-2-yl (S)-iso-propyl

The compounds encompassed within Category III of the present disclosurecan be prepared by the procedure outlined in Scheme V and described inExample 5 herein below.

EXAMPLE 64-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (17)

Preparation of{1-[1-(ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-methylpropyl}carbamicacid tert-butylester (16): To a solution of1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide,3, (0.200 g, 0.558 mmol),(S)-(2-tert-butoxycarbonylamino)-3-methylbutyric acid (0.133 g) and1-hydroxybenzotriazole (HOBt) (0.094 g) in DMF (5 mL) at 0°, is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.118 g) followedby diisopropylamine (0.151 g). The mixture is stirred at 0° C. for 30minutes then at room temperature overnight. The reaction mixture isdiluted with water and extracted with EtOAc. The combined organic phaseis washed with 1 N aqueous HCl, 5% aqueous NaHCO₃, water and brine, anddried over Na₂SO₄. The solvent is removed in vacuo to afford 0.219 g(82% yield) of the desired product which is used without furtherpurification. LC/MS ESI+ 477 (M+1).

Preparation of4-{(S)-2-[(S)-2-(tert-butoxycarbonyl)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid (17):{{1-[1-(ethylthiazol-2-yl)-2-(4-nitrophenyl)ethylcarbamoyl]-2-methylpropyl}carbamicacid tert-butylester, 16, (0.219 g) is dissolved in MeOH (4 mL). Acatalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 2 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (5 mL) and treatedwith SO₃-pyridine (0.146 g). The reaction is stirred at room temperaturefor 5 minutes after which a 7% solution of NH₄OH (30 mL) is added. Themixture is then concentrated and the resulting residue is purified byreverse phase chromatography to afford 0.148 g of the desired product asthe ammonium salt. ¹H(CD₃OD): δ 7.08 (s, 4H), 7.02 (s, 1H), 5.43 (s,1H), 3.85 (s, 1H), 3.28-2.77 (m, 4H), 1.94 (s, 1H), 1.46 (s, 9H), 1.29(s, 3H, J=7.3 Hz), 0.83 (s, 6H).

The following are further non-limiting examples of the second aspect ofCategory IV of the present disclosure.

(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamicacid: ¹H(CD₃OD): δ 7.09-6.91 (m, 5H), 5.30 (t, 1H, J=8.4 Hz), 3.60-2.64(m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5 Hz).

(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyl)acetamido]ethyl}phenyl-sulfamicacid: ¹H(CD₃OD): δ 7.12-7.07 (m, 4H), 7.03 (s, 1H), 5.42 (t, 1H, J=5.7Hz), 3.83-3.68 (q, 2H, J=11.4 Hz), 3.68 (s, 3H), 3.34-3.04 (m, 2H),2.83-2.76 (q, 2H, J=7.8 Hz), 1.31 (t, 3H, J=7.5 Hz).

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanamido]-ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.56 (d, 1H, J=7.8 Hz), 7.09 (s, 4H), 7.03 (s,1H), 5.26-5.20 (m, 1H), 3.90 (d, 1H, J=7.8 Hz), 3.70 (s, 3H), 3.30 (1H,A of ABX, obscured by solvent), 3.08 (1H, B of ABX, J=9.9, 9 Hz), 2.79(q, 2H, J=11.1, 7.2 Hz), 2.05-1.97 (m, 1H), 1.31 (t, 3H, J=7.5 Hz), 0.88(s, 3H), 0.85 (s, 3H), 0.79-0.75 (m, 1H).

4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ7.19-7.00 (m, 4H), 5.50-5.40 (m, 1H), 4.13-4.06(m, 1H), 3.32 (1H, A of ABX, J=7.5, 18 Hz), 3.12 (1H, B of ABX, J=8.1,13.8 Hz), 2.79 (q, 2H, J=7.8, 14.7 Hz), 1.70-1.55 (m, 1H), 1.46 (s, 9H),1.33 (t, 3H, J=2.7 Hz), 0.92 (q, 6H, J=6, 10.8 Hz).

4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentan-amido]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.12-7.03 (m, 5H), 6.84 (d, 1H, J=8.4 Hz), 5.40(t, 1H, J=5.7 Hz), 4.16 (t, 1H, J=6.3 Hz), 3.69 (s, 3H), 3.61-3.55 (m,1H), 3.29-3.27 (m, 1H), 3.14-3.07 (m, 1H), 2.81 (q, 2H, J=3.9, 11.2 Hz),1.66-1.59 (m, 1H), 1.48-1.43 (m, 2H), 1.31 (t, 3H, J=4.5 Hz), 0.96-0.90(m, 6H).

4-((S)-2-(4-Ethylthiazol-2-yl)-2-{(S)-2-[2-(methoxycarbonyl)acetamido]-3-phenylpropanamido}ethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.22-7.01 (m, 9H), 6.97 (s, 1H), 5.37-5.32 (m, 1H),4.64 (t, 1H, J=7.1 Hz), 3.71-3.68 (m, 2H), 3.64 (s, 3H), 3.28-3.26 (m,1H), 3.03-2.96 (m, 2H), 2.83-2.72 (m, 3H), 1.28 (t, 3H, J=7.5 Hz).

4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.06 (d, 1H, J=8.4 Hz), 7.61-7.58 (m, 1H), 7.57(s, 1H), 7.15 (t, 1H, J=0.6 Hz), 7.09-6.98 (m, 6H), 5.30-5.20 (m, 1H),4.10-4.00 (m, 1H), 3.19-3.13 (m, 2H), 1.63-1.55 (m, 2H), 1.48-1.33 (m,10H), 0.95-0.89 (m, 6H).

4-{(S)-2-[(S)-2-(Methoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid: ¹H NMR (CD₃OD) δ 8.22 (d, 1H, J=9 Hz), 7.62-7.57 (m, H), 7.15 (t,1H, J=0.6 Hz), 7.10-6.97 (m, 4H), 5.30-5.20 (m, 1H), 4.16-4.11 (m, 1H),3.67 (s, 2H), 3.22 (1H, A of ABX, J=6.9, 13.5 Hz), 3.11 (1H, B of ABX,J=7.8, 13.6 Hz), 1.65-1.58 (m, 1H), 1.50-1.45 (m, 2H), 0.95-0.88 (m,6H).

(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid: ¹H(CD₃OD): δ 7.09-6.91 (m, 5H), 5.30 (t, 1H, J=8.4 Hz), 3.60-2.64(m, 6H), 1.34 (s, 9H), 1.16 (t, 3H, J=7.5 Hz).

Category IV of the present disclosure relates to compounds having theformula:

wherein R is a substituted or unsubstituted thiophene-2-yl orthiophene-4-yl unit and non-limiting examples of R² are furtherdescribed in Table VII. TABLE VII No. R R² 151 thiazol-2-yl —OC(CH₃)₃152 4-methylthiazol-2-yl —OC(CH₃)₃ 153 4-ethylthiazol-2-yl —OC(CH₃)₃ 1544-cyclopropylthiazol-2-yl —OC(CH₃)₃ 155 4-tert-butylthiazol-2-yl—OC(CH₃)₃ 156 4-cyclohexylthiazol-2-yl —OC(CH₃)₃ 1574-(2,2,2-trifluoroethyl)thiazol-2-yl —OC(CH₃)₃ 1584-(3,3,3-trifluoropropyl)thiazol-2-yl —OC(CH₃)₃ 1594-(2,2-difluorocyclopropyl)thiazol-2-yl —OC(CH₃)₃ 1604,5-dimethylthiazol-2-yl —OC(CH₃)₃ 161 4-methyl-5-ethylthiazol-2-yl—OC(CH₃)₃ 162 4-phenylthiazol-2-yl —OC(CH₃)₃ 1634-(4-chlorophenyl)thiazol-2-yl —OC(CH₃)₃ 1644-(3,4-dimethylphenyl)thiazol-2-yl —OC(CH₃)₃ 1654-methyl-5-phenylthiazol-2-yl —OC(CH₃)₃ 1664-(thiophene-2-yl)thiazol-2-yl —OC(CH₃)₃ 167 thiazol-4-yl —OC(CH₃)₃ 1684-methylthiazol-4-yl —OC(CH₃)₃ 169 4-ethylthiazol-4-yl —OC(CH₃)₃ 1704-cyclopropylthiazol-4-yl —OC(CH₃)₃ 171 4-tert-butylthiazol-4-yl—OC(CH₃)₃ 172 4-cyclohexylthiazol-4-yl —OC(CH₃)₃ 1734-(2,2,2-trifluoroethyl)thiazol-4-yl —OC(CH₃)₃ 1744-(3,3,3-trifluoropropyl)thiazol-4-yl —OC(CH₃)₃ 1754-(2,2-difluorocyclopropyl)thiazol-4-yl —OC(CH₃)₃ 1764,5-dimethylthiazol-4-yl —OC(CH₃)₃ 177 4-methyl-5-ethylthiazol-4-yl—OC(CH₃)₃ 178 4-phenylthiazol-4-yl —OC(CH₃)₃ 1794-(4-chlorophenyl)thiazol-4-yl —OC(CH₃)₃ 1804-(3,4-dimethylphenyl)thiazol-4-yl —OC(CH₃)₃ 1814-methyl-5-phenylthiazol-4-yl —OC(CH₃)₃ 1824-(thiophene-2-yl)thiazol-4-yl —OC(CH₃)₃ 183 thiazol-2-yl —OCH₃ 1844-methylthiazol-2-yl —OCH₃ 185 4-ethylthiazol-2-yl —OCH₃ 1864-cyclopropylthiazol-2-yl —OCH₃ 187 4-tert-butylthiazol-2-yl —OCH₃ 1884-cyclohexylthiazol-2-yl —OCH₃ 189 4-(2,2,2-trifluoroethyl)thiazol-2-yl—OCH₃ 190 4-(3,3,3-trifluoropropyl)thiazol-2-yl —OCH₃ 1914-(2,2-difluorocyclopropyl)thiazol-2-yl —OCH₃ 1924,5-dimethylthiazol-2-yl —OCH₃ 193 4-methyl-5-ethylthiazol-2-yl —OCH₃194 4-phenylthiazol-2-yl —OCH₃ 195 4-(4-chlorophenyl)thiazol-2-yl —OCH₃196 4-(3,4-dimethylphenyl)thiazol-2-yl —OCH₃ 1974-methyl-5-phenylthiazol-2-yl —OCH₃ 198 4-(thiophene-2-yl)thiazol-2-yl—OCH₃ 199 thiazol-4-yl —OCH₃ 200 4-methylthiazol-4-yl —OCH₃ 2014-ethylthiazol-4-yl —OCH₃ 202 4-cyclopropylthiazol-4-yl —OCH₃ 2034-tert-butylthiazol-4-yl —OCH₃ 204 4-cyclohexylthiazol-4-yl —OCH₃ 2054-(2,2,2-trifluoroethyl)thiazol-4-yl —OCH₃ 2064-(3,3,3-trifluoropropyl)thiazol-4-yl —OCH₃ 2074-(2,2-difluorocyclopropyl)thiazol-4-yl —OCH₃ 2084,5-dimethylthiazol-4-yl —OCH₃ 209 4-methyl-5-ethylthiazol-4-yl —OCH₃210 4-phenylthiazol-4-yl —OCH₃ 211 4-(4-chlorophenyl)thiazol-4-yl —OCH₃212 4-(3,4-dimethylphenyl)thiazol-4-yl —OCH₃ 2134-methyl-5-phenylthiazol-4-yl —OCH₃ 214 4-(thiophene-2-yl)thiazol-4-yl—OCH₃ 215 thiazol-2-yl —CH₃ 216 4-methylthiazol-2-yl —CH₃ 2174-ethylthiazol-2-yl —CH₃ 218 4-cyclopropylthiazol-2-yl —CH₃ 2194-tert-butylthiazol-2-yl —CH₃ 220 4-cyclohexylthiazol-2-yl —CH₃ 2214-(2,2,2-trifluoroethyl)thiazol-2-yl —CH₃ 2224-(3,3,3-trifluoropropyl)thiazol-2-yl —CH₃ 2234-(2,2-difluorocyclopropyl)thiazol-2-yl —CH₃ 2244,5-dimethylthiazol-2-yl —CH₃ 225 4-methyl-5-ethylthiazol-2-yl —CH₃ 2264-phenylthiazol-2-yl —CH₃ 227 4-(4-chlorophenyl)thiazol-2-yl —CH₃ 2284-(3,4-dimethylphenyl)thiazol-2-yl —CH₃ 2294-methyl-5-phenylthiazol-2-yl —CH₃ 230 4-(thiophene-2-yl)thiazol-2-yl—CH₃ 231 thiazol-4-yl —CH₃ 232 4-methylthiazol-4-yl —CH₃ 2334-ethylthiazol-4-yl —CH₃ 234 4-cyclopropylthiazol-4-yl —CH₃ 2354-tert-butylthiazol-4-yl —CH₃ 236 4-cyclohexylthiazol-4-yl —CH₃ 2374-(2,2,2-trifluoroethyl)thiazol-4-yl —CH₃ 2384-(3,3,3-trifluoropropyl)thiazol-4-yl —CH₃ 2394-(2,2-difluorocyclopropyl)thiazol-4-yl —CH₃ 2404,5-dimethylthiazol-4-yl —CH₃ 241 4-methyl-5-ethylthiazol-4-yl —CH₃ 2424-phenylthiazol-4-yl —CH₃ 243 4-(4-chlorophenyl)thiazol-4-yl —CH₃ 2444-(3,4-dimethylphenyl)thiazol-4-yl —CH₃ 2454-methyl-5-phenylthiazol-4-yl —CH₃ 246 4-(thiophene-2-yl)thiazol-4-yl—CH₃

The compounds encompassed within Category IV of the present disclosurecan be prepared by the procedure outlined in Scheme VI and described inExample 7 herein below.

EXAMPLE 7[1-(S)-(Phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acidtert-butyl ester (19)

Preparation of[2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]-carbamic acidtert-butyl ester (18): A mixture of[2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butylester, 2, (0.343 g, 1.05 mmol), 2-bromo-acetophenone (0.231 g, 1.15mmol), in CH₃CN (5 mL) is refluxed 1.5 hour. The solvent is removedunder reduced pressure and the residue re-dissolved in CH₂Cl₂ thenpyridine (0.24 mL, 3.0 mmol) and Boc₂O (0.24 mL, 1.1 mmol) are added.The reaction is stirred for 2 hours and diethyl ether is added to thesolution and the precipitate which forms is removed by filtration. Theorganic layer is dried (Na₂SO₄), filtered, and concentrated to a residuewhich is purified over silica to afford 0.176 g (39%) of the desiredproduct ESI+MS 426 (M+1).

Preparation of[1-(S)-(phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acidtert-butyl ester (19):[2-(4-nitrophenyl)-1-(S)-(4-phenylthiazol-2-yl)ethyl]-carbamic acidtert-butyl ester, 18, (0.176 g, 0.41 mmol) is dissolved in MeOH (4 mL).A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirredunder a hydrogen atmosphere 12 hours. The reaction mixture is filteredthrough a bed of CELITE™ and the solvent is removed under reducedpressure. The crude product is dissolved in pyridine (12 mL) and treatedwith SO₃-pyridine (0.195 g, 1.23 mmol). The reaction is stirred at roomtemperature for 5 minutes after which a 7% solution of NH₄OH (10 mL) isadded. The mixture is then concentrated and the resulting residue ispurified by reverse phase chromatography to afford 0.080 g of thedesired product as the ammonium salt. ¹H NMR (300 MHz, MeOH-d₄) δ 7.93(d, J=6.0 Hz, 2H), 7.68 (s, 1H), 7.46-7.42 (m, 3H), 7.37-7.32 (m, 1H),7.14-7.18 (m, 3H), 5.13-5.18 (m, 1H), 3.40 (dd, J=4.5 and 15.0 Hz, 1H),3.04 (dd, J=9.6 and 14.1 Hz, 1H), 1.43 (s, 9H).

The following are further non-limiting examples of Category IV of thepresent disclosure.

(S)-4-(2-(4-Methylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H (CD₃OD): δ 7.31 (s, 4H), 7.20 (s, 1H), 5.61-5.56 (m, 1H), 3.57-3.22(m, 2H), 2.62 (s, 3H), 1.31 (s, 3H).

(S)-4-(2-(4-Ethylthiazol-2-yl)-2-pivalamideoethyl)phenylsulfamic acid:¹H NMR (300 MHz, MeOH-d₄) δ 7.92 (d, J=8.1 Hz, 1H), 7.12-7.14 (m, 4H),7.03 (s, 1H), 5.38-5.46 (m, 1H), 3.3-3.4 (m, 1H), 3.08 (dd, J=10.2 and13.8 Hz, 1H), 2.79 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.13 (s,9H).

(S)—N-(1-(4-Hydroxymethyl)thiazol-2-yl)-2pivalamidoethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.92 (d, J=8.1 Hz, 1H), 7.24 (s, 1H),7.08 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.29-5.37 (m, 1H), 4.55(s, 2H), 3.30 (dd, J=4.8 and 13.5 Hz, 1H), 2.99 (dd, J=10.5 and 13.5 Hz,1H), 0.93 (s, 9H).

(S)-4-(2-(4-Ethoxycarbonyl)thiazol-2-yl)-2-pivalamideoethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 8.30 (s, 1H), 8.04 (d, J=8.1 Hz, 1H),7.13 (s, 4H), 5.41-5.49 (m, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.43 (dd, J=5.1and 13.8 Hz, 1H), 3.14 (dd, J=5.7 and 9.9 Hz, 1H), 1.42 (t, J=7.2 Hz,3H), 1.14 (s, 9H).

(S)-4-(2-(4-Phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid:¹H NMR (300 MHz, MeOH-d₄) δ 7.94-8.01 (m, 3H), 7.70 (s, 1H), 7.42-7.47(m, 2H), 7.32-7.47 (m, 1H), 7.13-7.20 (m, 3H), 5.48-5.55 (m, 1H), 3.50(dd, J=5.1 and 14.1 Hz, 1H), 3.18 (dd, J=10.2 and 14.1 Hz, 1H), 1.67 (s,9H).

4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.96-7.93 (d, 1H, J=8.1 Hz), 7.69 (s, 1H), 7.51-7.49(d, 2H, J=7.9 Hz), 7.33 (t, 1H, J=8.0 Hz), 7.14 (s, 4H), 6.92-6.90 (d,1H, J=7.8 Hz), 5.50 (t, 1H, J=5.1 Hz), 3.87 (s, 3H), 3.50-3.13 (m, 2H),1.15 (s, 9H).

4-((S)-2-(4-(3-methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.98-7.85 (m, 3H), 7.53 (s, 1H), 7.26-7.12 (m, 3H),7.03-6.98 (m, 2H), 5.54-5.46 (m, 1H), 3.52-3.13 (m, 2H), 1.15 (s, 9H).

4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamicacid: ¹H(CD₃OD): δ 8.11-8.09 (d, 1H, J=7.8 Hz), 7.96-7.93 (d, 1H, J=8.4Hz), 7.74 (s, 1H), 7.18-7.16 (m, 4H), 6.67-6.64 (d, 2H, J=9.0 Hz),5.55-5.47 (m, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.52-3.13 (m, 2H), 1.17(s, 9H).

(S)-4-(2-(4-Benzylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid ¹HNMR (CD₃OD) δ 7.85 (d, 1H, J=8.4 Hz), 7.38-7.20 (m, 4H), 7.11-7.02 (m,1H), 7.00 (s, 1H), 5.42-5.37 (m, 1H), 4.13 (s, 2H), 3.13-3.08 (m, 2H),1.13 (s, 9H).

(S)-4-(2-Pivalamido-2-(4-(thiophen-2-ylmethyl)thiazol-2-yl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.88-7.85 (d, 1H), 7.38-7.35 (m, 1H), 7.10-7.01(m, 4H), 7.02 (s, 1H), 5.45-5.38 (m, 1H), 4.13 (s, 2H), 3.13-3.05 (m,2H), 1.13 (2, 9H).

(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.85 (d, 1H, J=8.4 Hz), 7.25-7.20 (m, 1H),7.11-7.02 (m, 4H), 7.01 (s, 1H), 6.90-6.79 (m, 2H), 5.45-5.40 (m, 1H),4.09 (s, 2H), 3.79 (s, 3H), 3.12-3.08 (m, 2H), 1.10 (s, 9H).

4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.53 (s, 1H), 7.45 (s, 1H), 7.42-7.40 (d, 1H, J=8.4Hz), 7.19-7.15 (m, 4H), 6.91-6.88 (d, 2H, J=8.4 Hz), 5.51-5.46 (m, 1H),4.30 (s, 4H), 3.51-3.12 (m, 2H), 1.16 (s, 9H).

(S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 7.63-7.60 (d, 2H, J=7.1 Hz), 7.49-7.35 (m, 3H), 7.14(s, 4H), 5.43-5.38 (m, 1H), 3.42-3.09 (m, 2H), 2.49 (s, 3H), 1.14 (s,9H).

(S)-4-(2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid: ¹H(CD₃OD): δ 8.04-8.01 (m, 2H), 7.72-7.66 (m, 5H), 7.48-7.35 (m,3H), 7.15 (s, 4H), 5.50 (t, 1H, J=5.0 Hz), 3.57-3.15 (d, 2H), 1.16 (s,9H).

(S)-4-(2-tert-Butoxycarbonyl-2-(2-methylthaizol-4-yl)-phenylsulfamicacid ¹H NMR (300 MHz, D₂O) δ 6.99-7.002 (m, 4H), 6.82 (s, 1H), 2.26 (dd,J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8 and 7.2 Hz, 1H), 2.48 (s, 3H),1.17 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-propylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.18-7.02 (m, 5H), 5.06-5.03(m, 1H), 3.26 (dd, J=13.8, 4.8 Hz, 1H), 2.95 (dd, J=13.8, 9.3 Hz, 1H),2.74 (dd, J=15.0, 7.2 Hz, 2H), 1.81-1.71 (m, 2H), 1.40 (s, 7H), 1.33(bs, 2H), 0.988 (t, J=7.5 Hz 3H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-tert-butylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.12 (s, 4H), 7.01 (s, 1H),5.11-5.06 (m, 1H), 3.32-3.25 (m, 1H), 2.96 (m, 1H), 1.42 (s, 8H), 1.38(s, 9H), 1.32 (s, 1H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.36 (s, 1H), 7.14-7.05 (m,4H), 5.06 (dd, J=9.0, 5.1 Hz, 1H), 4.55 (s, 2H), 3.42 (s, 3H), 3.31-3.24(m, 1H), 2.97 (dd, J=13.8, 9.9 Hz, 1H), 1.47-1.31 (m, 9H).

(S)-4-(2-tert-Butoxycarbonyl)-2-(4-(2-hydroxymethyl)thiazol-2yl)ethyl)phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.22-7.25 (m, 1H), 7.09-7.15 (m, 4H),5.00-5.09 (m, 1H), 4.32-4.35 (m, 1H), 3.87 (t, J=6.6 Hz, 2H), 3.23-3.29(m, 1H), 3.09-3.18 (m, 1H), 2.98 (t, J=6.6 Hz, 2H), 1.41 (s, 9H).

(S)-4-(2-tert-Butoxycarbonyl)-2-(4-(2-ethoxy-2-oxoethyl)-thiazole-2-yl)-ethyl)phenylsulfamic acid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.29 (s, 1H), 7.09-7.16(m, 4H), 5.04-5.09 (m, 1H), 4.20 (q, J=6.9 Hz, 2H), 3.84 (s, 2H), 3.30(dd, J=4.8 and 14.1 Hz, 1H), 2.97 (dd, J=9.6 Hz and 13.8 Hz, 1H), 1.41(s, 9H), 1.29 (t, J=7.2 Hz, 3H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(2-(2-methoxy-2-oxoyethylamino)-2-oxoethyl)thiazole-2-yl)ethyl)phenylsulfamic acid: ¹H NMR (300MHz, MeOH-d₄) δ 7.31 (s, 1H), 7.01-7.16 (m, 4H), 5.04-5.09 (m, 1H), 4.01(s, 2H), 3.78 (s, 2H), 3.74 (s, 3H), 3.29 (dd, J=5.1 and 13.8 Hz, 1H),2.99 (dd, J=9.3 and 13.8 Hz, 1H), 1.41 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(2-pivalamidothiazol-4-yl)ethyl)phenyl-sulfamicacid: ¹H NMR (300 MHz, D₂O) δ 6.95 (s, 4H), 6.63 (s, 1H), 2.94 (dd,J=13.5 and 4.8 Hz, 1H), 2.75 (dd, J=13.5 and 4.8 Hz, 1H), 1.16 (s, 9H),1.13 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonyl)-2-(5-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.62 (d, J=7.2Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs, 1H), 3.07-2.99 (m,2H), 1.43 (s, 9H).

4-((S)-2-(tert-Butoxycarbonyl)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 8.28 (s, 1H), 8.22-8.19 (m,1H), 7.89 (s, 1H), 7.65 (d, J=5.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.15(s, 4H), 5.17-5.14 (m, 1H), 3.43-3.32 (m, 1H), 3.05 (dd, J=14.1, 9.6 Hz,1H), 1.42 (s, 9H).

(S)-4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.98 (s, 1H), 7.94 (d, J=7.2Hz, 2H), 7.46-7.35 (m, 4H), 7.14 (s, 4H), 5.09 (bs, 1H), 3.07-2.99 (m,2H), 1.43 (s, 9H).

(S)-{4-[2,2-Dimethyl-propionylamino)-2-(2-phenyl-thiazole-4-yl)ethyl]phenyl}-sulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.92-7.96 (m, 2H), 7.65 (d, J=8.4 Hz,1H), 7.45-7.49 (m, 3H), 7.18 (s, 1H), 7.08-7.15 (m, 4H), 5.34-5.41 (m,1H), 3.26 (dd, J=14.1 and 6.0 Hz, 1H), 3.08 (dd, J=13.8 and 9.0 Hz, 1H),1.47 (s, 9H).

(S)-4-(2-tert-Butoxycarbonylamido)-2-(4-phenyl)-2-(4-phenylthiazole-2-yl)ethyl)-phenylsulfamicacid: ¹H NMR (300 MHz, MeOH-d₄) δ 7.93 (d, J=6.0 Hz, 2H), 7.68 (s, 1H),7.46-7.42 (m, 3H), 7.37-7.32 (m, 1H), 7.14-7.18 (m, 3H), 5.13-5.18 (m,1H), 3.40 (dd, J=4.5 and 15.0 Hz, 1H), 3.04 (dd, J=9.6 and 14.1 Hz, 1H),1.43 (s, 9H).

(S,S)-2-(2-{2-[2-tert-Butoxycarbonylamino-2-(4-sulfoaminophenyl)ethyl]thiazol-4-yl}acetylamido)-3-phenylpropionicacid methyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 6.85-6.94 (m, 9H), 6.64(s, 1H), 4.83 (s, 1H), 4.54-4.58 (m, 1H), 3.49 (s, 3H), 3.39 (s, 2H),2.80-2.97 (m, 1H), 2.64-2.78 (m, 1H), 1.12 (s, 9H).

(S)-[1-{1-Oxo-4-[2-(1-phenyl-1H-tetrazol-5-sulfonyl)ethyl]-1H-1λ⁴-thiazol-2-yl}-2-(4-sulfamino-phenyl)-ethyl]-carbamicacid tert-butyl ester: ¹H NMR (300 MHz, MeOH-d₄) δ 7.22-7.75 (m, 2H),7.62-7.69 (m, 2H), 7.55 (s, 1H), 7.10-7.20 (m, 5H), 5.25 (m, 1H),4.27-4.36 (m, 1H), 4.11-4.21 (m, 1H), 3.33-3.44 (m, 4H), 2.84-2.90 (m,1H), 1.33 (s, 9H).

4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenylsulfamic acid: ¹H NMR (300 MHz, CD₃OD): δ 7.84 (dd, J=3.0, 1.5 Hz, 1H),7.57-7.55 (m, 2H), 7.47 (dd, J=4.8, 3.0 Hz, 1H), 7.15 (s, 4H), 5.15-5.10(m, 1H), 3.39-3.34 (m, 1H), 3.01 (dd, J=14.1, 9.6 Hz, 1H), 1.42 (s, 8H),1.32 (s, 1H).

(S)-4-(2-(Benzo[d]thiazol-2-ylamino)-2-(tert-butoxycarbonyl)ethyl)phenylsulfamicacid: ¹H NMR (CD₃OD) δ 7.86-7.82 (m, 2H), 7.42 (t, 2H, J=7.1 Hz), 7.33(t, 1H, J=8.2 Hz), 7.02 (s, 4H), 5.10-5.05 (m, 1H), 2.99-2.91 (m, 2H),1.29 (s, 9H).

(S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)-phenylsulfamicacid ¹H NMR (300 MHz, D₂O) δ 6.99-7.002 (m, 4H), 6.82 (s, 1H), 2.26 (dd,J=13.8 and 7.2 Hz, 1H), 2.76 (dd, J=13.8 and 7.2 Hz, 1H), 2.48 (s, 3H),1.17 (s, 9H).

Regulation of HPTP-β provides a means for modulating the activity ofangiopoietin receptor-type tyrosine kinase Tie-2, and thereby mediatedisease states wherein angiogenesis is improperly regulated by the humanbody. The compounds of the present disclosure serve as a means forproviding regulation of angiogenesis. As such the present disclosureaddresses several unmet medical needs, inter alia;

-   1) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby provide a means    for regulating angiogenesis in a disorder wherein angiogenesis is    elevated;-   2) Providing compositions effective as human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby provide a means    for regulating angiogenesis in a disorder; and-   3) Providing compositions effective human protein tyrosine    phosphatase beta (HPTP-β) inhibitors; and thereby provide a means    for regulating angiogenesis in a disorder wherein angiogenesis is    decreased.

For purposes of the present disclosure the term “regulate” is defined asin its accepted dictionary meanings. Thus, the meaning of the term“regulate” includes, but is not limited to, up-regulate ordown-regulate, to fix, to bring order or uniformity, to govern, or todirect by various means. In one aspect, an antibody may be used in amethod for the treatment of an “angiogenesis elevated disorder” or“angiogenesis reduced disorder”. As used herein, an “angiogenesiselevated disorder” is one that involves unwanted or elevatedangiogenesis in the biological manifestation of the disease, disorder,and/or condition; in the biological cascade leading to the disorder; oras a symptom of the disorder. Similarly, the “angiogenesis reduceddisorder” is one that involves wanted or reduced angiogenesis in thebiological manifestations. This “involvement” of angiogenesis in anangiogenesis elevated/reduced disorder includes, but is not limited to,the following:

-   1. The angiogenesis as a “cause” of the disorder or biological    manifestation, whether the level of angiogenesis is elevated or    reduced genetically, by infection, by autoimmunity, trauma,    biomechanical causes, lifestyle, or by some other causes.-   2. The angiogenesis as part of the observable manifestation of the    disease or disorder. That is, the disease or disorder is measurable    in terms of the increased or reduced angiogenesis. From a clinical    standpoint, angiogenesis indicates the disease; however,    angiogenesis need not be the “hallmark” of the disease or disorder.-   3. The angiogenesis is part of the biochemical or cellular cascade    that results in the disease or disorder. In this respect, regulation    of angiogenesis may interrupt the cascade, and may control the    disease. Non-limiting examples of angiogenesis regulated disorders    that may be treated by the present disclosure are herein described    below.

Formulations

The present disclosure also relates to compositions or formulationswhich comprise the Kv1.5 potassium channel inhibitors according to thepresent disclosure. In general, the compositions of the presentdisclosure comprise:

-   -   a) an effective amount of one or more phenylsufamic acids and        salts thereof according to the present disclosure which are        effective as human protein tyrosine phosphatase beta (HPTP-β)        inhibitors; and    -   b) one or more excipients.

For the purposes of the present disclosure the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent disclosure and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present disclosure have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

Non-limiting examples of compositions according to the presentdisclosure include:

-   -   a) from about 0.001 mg to about 1000 mg of one or more        phenylsulfamic acids according to the present disclosure; and    -   b) one or more excipients.

Another embodiment according to the present disclosure relates to thefollowing compositions:

-   -   a) from about 0.01 mg to about 100 mg of one or more        phenylsulfamic acids according to the present disclosure; and    -   b) one or more excipients.

A further embodiment according to the present disclosure relates to thefollowing compositions:

-   -   a) from about 0.1 mg to about 10 mg of one or more        phenylsulfamic acids according to the present disclosure; and    -   b) one or more excipients.

The term “effective amount” as used herein means “an amount of one ormore phenylsulfamic acids, effective at dosages and for periods of timenecessary to achieve the desired or therapeutic result.” An effectiveamount may vary according to factors known in the art, such as thedisease state, age, sex, and weight of the human or animal beingtreated. Although particular dosage regimes may be described in examplesherein, a person skilled in the art would appreciated that the dosageregime may be altered to provide optimum therapeutic response. Thus, itis not possible to specify an exact “effective amount.” For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. In addition, the compositions of the present disclosure canbe administered as frequently as necessary to achieve a therapeuticamount.

Method of Use

The present disclosure relates to methods for regulating angiogenesis ina human comprising administering to a human one or more of the disclosedcompounds.

One example of the disclosed methods includes a method for treating anangiogenesis regulated disorder in a subject, wherein the angiogenesisregulated disorder is an angiogenesis elevated disorder, and saiddisorder is chosen from diabetic retinopathy, macular degeneration,cancer, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum,Paget's disease, vein occlusion, artery occlusion, carotid obstructivedisease, chronic uveitis/vitritis, mycobacterial infections, Lyme'sdisease, systemic lupus erythematosis, retinopathy of prematurity,Eales' disease, Behcet's disease, infections causing a retinitis orchoroiditis, presumed ocular histoplasmosis, Best's disease, myopia,optic pits, Stargardt's disease, pars planitis, chronic retinaldetachment, hyperviscosity syndrome, toxoplasmosis, trauma andpost-laser complications, diseases associated with rubeosis, andproliferative vitreoretinopathy.

Another example of the disclosed methods includes a method for treatingan angiogenesis regulated disorder in a subject, wherein theangiogenesis regulated disorder is an angiogenesis elevated disorder,and said disorder is chosen from inflammatory bowel diseases such asCrohn's disease and ulcerative colitis, psoriasis, sarcoidosis,rheumatoid arthritis, hemangiomas, Osler-Weber-Rendu disease, orhereditary hemorrhagic telangiectasia, solid or blood borne tumors andacquired immune deficiency syndrome.

A further example of the disclosed methods includes a method fortreating an angiogenesis regulated disorder in a subject wherein theangiogenesis regulated disorder is an angiogenesis reduced disorder andchosen from skeletal muscle and myocardial ischemia, stroke, coronaryartery disease, peripheral vascular disease, coronary artery disease.

A yet further example of the disclosed methods includes a method ofvascularizing ischemic tissue. As used herein, “ischemic tissue,” meanstissue that is deprived of adequate blood flow. Examples of ischemictissue include, but are not limited to, tissue that lack adequate bloodsupply resulting from myocardial and cerebral infarctions, mesenteric orlimb ischemia, or the result of a vascular occlusion or stenosis. In oneexample, the interruption of the supply of oxygenated blood may becaused by a vascular occlusion. Such vascular occlusion may be caused byarteriosclerosis, trauma, surgical procedures, disease, and/or otheretiologies. Also included within the methods of treatment of the presentdisclosure is the treatment of skeletal muscle and myocardial ischemia,stroke, coronary artery disease, peripheral vascular disease, coronaryartery disease.

A still further example of the disclosed methods includes a method ofrepairing tissue. As used herein, “repairing tissue” means promotingtissue repair, regeneration, growth, and/or maintenance including, butnot limited to, wound repair or tissue engineering. One skilled in theart appreciates that new blood vessel formation is required for tissuerepair. In turn, tissue may be damaged by, including, but not limitedto, traumatic injuries or conditions including arthritis, osteoporosisand other skeletal disorders, and burns. Tissue may also be damaged byinjuries due to surgical procedures, irradiation, laceration, toxicchemicals, viral infection or bacterial infections, or burns. Tissue inneed of repair also includes non-healing wounds. Examples of non-healingwounds include non-healing skin ulcers resulting from diabeticpathology; or fractures that do not heal readily.

The disclosed compounds are also suitable for use in effecting tissuerepair in the context of guided tissue regeneration (GTR) procedures.Such procedures are currently used by those skilled in the arts toaccelerate wound healing following invasive surgical procedures.

A yet still further example of the disclosed methods includes a methodof promoting tissue repair characterized by enhanced tissue growthduring the process of tissue engineering. As used herein, “tissueengineering” is defined as the creation, design, and fabrication ofbiological prosthetic devices, in combination with synthetic or naturalmaterials, for the augmentation or replacement of body tissues andorgans. Thus, the present methods may be used to augment the design andgrowth of human tissues outside the body for later implantation in therepair or replacement of diseased tissues. For example, antibodies maybe useful in promoting the growth of skin graft replacements that areused as a therapy in the treatment of burns.

Other examples of the tissue engineering example of the disclosedmethods includes in cell-containing or cell-free devices that induce theregeneration of functional human tissues when implanted at a site thatrequires regeneration. As discussed herein, biomaterial-guided tissueregeneration may be used to promote bone re-growth in, for example,periodontal disease. Thus, antibodies may be used to promote the growthof reconstituted tissues assembled into three-dimensional configurationsat the site of a wound or other tissue in need of such repair.

A yet further example of the tissue engineering example of the disclosedmethods, the compounds disclosed herein can be included in external orinternal devices containing human tissues designed to replace thefunction of diseased internal tissues. This approach involves isolatingcells from the body, placing them with structural matrices, andimplanting the new system inside the body or using the system outsidethe body. For example, antibodies may be included in a cell-linedvascular graft to promote the growth of the cells contained in thegraft. It is envisioned that the methods of the disclosure may be usedto augment tissue repair, regeneration and engineering in products suchas cartilage and bone, central nervous system tissues, muscle, liver,and pancreatic islet (insulin-producing) cells.

The present disclosure also relates to the use of the disclosedphenylsulfamic acids in the manufacture of a medicament for promotingthe growth of skin graft replacements.

The present disclosure also relates to the use of the disclosedphenylsulfamic acids according to the present disclosure in themanufacture of a medicament for use in effecting tissue repair in thecontext of guided tissue regeneration (GTR) procedures.

The disclosed compounds can be used in the manufacture of one or moremedicaments, non-limiting examples of these medicaments are:

Medicaments for the treatment an angiogenesis regulated disorder in asubject, wherein the angiogenesis regulated disorder is an angiogenesiselevated disorder.

Medicaments for the treatment an angiogenesis regulated disorder in asubject, wherein the angiogenesis regulated disorder is an angiogenesiselevated disorder chosen from Crohn's disease and ulcerative colitis,psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas,Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia,solid or blood borne tumors and acquired immune deficiency syndrome.

Medicaments useful for the purposes of tissue engineering therebyinducing enhanced tissue growth.

Medicaments for the treatment an angiogenesis regulated disorder in asubject, wherein the angiogenesis regulated disorder is an angiogenesisreduced disorder.

Procedures Screening Assays Using In Vitro and In Vivo Models ofAngiogenesis

Antibodies of the disclosure may be screened in angiogenesis assays thatare known in the art. Such assays include in vitro assays that measuresurrogates of blood vessel growth in cultured cells or formation ofvascular structures from tissue explants and in vivo assays that measureblood vessel growth directly or indirectly (Auerbach, R., et al. (2003).Clin Chem 49, 32-40, Vailhe, B., et al. (2001). Lab Invest 81, 439-452).

1. In Vitro Models of Angiogenesis

The in vitro models which are suitable for use in the present disclosureemploy cultured endothelial cells or tissue explants and measure theeffect of agents on “angiogenic” cell responses or on the formation ofblood capillary-like structures. Non-limiting examples of in vitroangiogenesis assays include but are not limited to endothelial cellmigration and proliferation, capillary tube formation, endothelialsprouting, the aortic ring explant assay and the chick aortic archassay.

2. In Vivo Models of Angiogenesis

The in vivo agents or antibodies which are suitable for use in thepresent disclosure are administered locally or systemically in thepresence or absence of growth factors (i.e. VEGF or angiopoietin 1) andnew blood vessel growth is measured by direct observation or bymeasuring a surrogate marker such as hemoglobin content or a fluorescentindicator. Non-limiting examples of in vitro angiogenesis assays includebut are not limited to chick chorioallantoic membrane assay, the cornealangiogenesis assay, and the Matrigel® plug assay.

3. Procedures for Determining Vascularization of Ischemic Tissue.

Standard routine techniques are available to determine if a tissue is atrisk of suffering ischemic damage from undesirable vascular occlusion.For example, in myocardial disease these methods include a variety ofimaging techniques (e.g., radiotracer methodologies, x-ray, and MRI) andphysiological tests. Therefore, induction of angiogenesis as aneffective means of preventing or attenuating ischemia in tissuesaffected by or at risk of being affected by a vascular occlusion can bereadily determined.

A person skilled in the art of using standard techniques may measure thevascularization of tissue. Non-limiting examples of measuringvascularization in a subject include SPECT (single photon emissioncomputed tomography); PET (positron emission tomography); MRI (magneticresonance imaging); and combination thereof, by measuring blood flow totissue before and after treatment. Angiography may be used as anassessment of macroscopic vascularity. Histologic evaluation may be usedto quantify vascularity at the small vessel level. These and othertechniques are discussed in Simons, et al., “Clinical trials in coronaryangiogenesis,” Circulation, 102, 73-86 (2000).

The following are non-limiting examples of HPTPβ (IC₅₀ μM) and PTP1B(IC₅₀ μM) activity is listed herein below in Table VIII. TABLE VIIIHPTPβ PTP1B Compound IC₅₀ μM IC₅₀ μM

0.000157 0.722(S)-{4-[2-(4-Ethylthiazol-2-yl)-2-(phenylacetylamino)ethyl]-phenyl}sulfamic acid

0.004 7.12 4-{(S)-2-[(R)-2-(tert-butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid

0.031 7.05 {1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-carbamoyl]-(S)-2-phenylethyl}methyl carbamic acid tert-butyl ester

<5 × 10⁻⁸ 0.754 {1-[1-(5-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methyl carbamic acidtert-butyl ester

<5 × 10⁻⁸ 0.905 4-{(S)-2-(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanamido-2-(2-phenylthiazol-4-yl)}phenylsulfamic acid

0.000162 0.494-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

0.006 1.02 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(thiazol-2-yl)ethyl}phenylsulfamic acid

0.001 0.48 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-methylthiazol-2-yl)ethyl}phenylsulfamic acid

0.0001 1.03 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-propylthiazol-2-yl)ethyl}phenylsulfamic acid

0.0002 0.7084-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

0.00001 0.3 4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

<5 × 10⁻⁸ 1.784-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamic acid

0.001 0.314-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamic acid

0.0001 1.12 4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamic acid

0.0003 1.63 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic acid

0.00008 0.124-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido)-2-[4-(3,3,3-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamic acid

0.001 0.64 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(methoxymethyl)thiazol-2-yl]ethyl}phenylsulfamic acid

0.0002 0.07 4-{(S)-2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

0.0003 0.81 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(5-phenylthiazol-2-yl)ethyl}phenylsulfamic acid

<5 × 10⁻⁸ 0.394-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamic acid

<2 × 10⁻⁶ 0.5974-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-phenylthiazol-2-yl)ethyl}phenylsulfamic acid

<5 × 10⁻⁸ 0.994-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yl]ethyl}phenylsulfamic acid

0.00009 0.444-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid

0.001 0.18 4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

0.0004 0.089 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamic acid

<5 × 10⁻⁸ 0.374-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]phenyl-sulfamic acid

0.00014 0.68 4-{(S)-2-[(S)-2-(Ethoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid

0.0001 1.01 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-(thylthiazol-4-yl)ethyl}phenylsulfamic acid

0.001 1.16 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-(ethylthiazol-4-yl)ethyl}phenylsulfamic acid

0.0002 1.35 4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

0.00008 2.544-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy-carbonyl)-3- phenylpropanamido]ethyl}phenylsulfamic acid

0.002 1.21 4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

7 × 10⁻⁷ 0.5084-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropionamido]-2-(2-(henylthiazole-4-yl)ethyl}phenylsulfamic acid

5 × 10⁻⁸ 0.6044-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid

<5 × 10⁻⁸ 0.954-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

<5 × 10⁻⁸ 1.094-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid

0.0004 5 4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamic acid

0.003 0.295 4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(pyrazin-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid

0.001 1.97 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamic acid

0.0003 1.52 4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamic acid

0.00024 1.16 4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamic acid

0.006 1.064-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid

0.028 16.0(S)-4-{2-2-(tert-Butoxycarbonyl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid

0.020 5.26 (S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyl)acetamido]ethyl}phenylsulfamic acid

0.003 1.03 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanamido]-ethyl}phenylsulfamic acid

0.001 0.48 4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamic acid

0.0003 0.07 4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentanamido]ethyl}phenylsulfamic acid

0.0003 0.2994-((S)-2-(4-Ethylthiazol-2-yl)-2-{(S)-2-[2-(methoxycarbonyl)-acetamido]-3-phenylpropanamido}ethyl)phenylsulfamic acid

<5 × 10⁻⁸ 0.524-{(S)-2-[(S)-2-(Methoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamic acid

0.028 16.0(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamido]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamic acid

0.049 33.02 [1-(S)-(Phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acid tert-butyl ester

0.112 50 (S)-4-(2-(4-Methylthiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamic acid

0.085 142 (S)-4-(2-(4-Ethylthiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamic acid

0.266 50 (S)-4-{2-[4-(hydroxymethyl)thiazol-2-yl]-2-pivalamidoethyl}phenyl-sulfamic acid

0.584 44.9 (S)-4-{[2-(4-Ethoxycarbonyl)thiazol-2-yl]-2-pivalamidoethyl}phenylsulfamic acid

0.042 82.3 (S)-4-(2-(4-Phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid

0.110 40.1 4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid

0.086 43.1 4-((S)2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamic acid

0.113 38.2 (S)-4-(2-(4-Benzylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid

0.132 50 (S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid

0.138 38.34-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid

0.098 50.5 (S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)pheylsulfamic acid

0.381 28.6 (S)-4-(2-(4-(Biphen-4-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid

0.033 18.9 (S)-4-(2-tert-Butoxycarbonylamino)-2-(2-methylthiazol-4-yl)ethyl)phenylsulfamic acid

0.04 35.6 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-propylthiazol-2-yl)ethyl)phenyl sulfamic acid

0.027 50 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-tert-butylthiazol-2-yl)ethyl)phenyl sulfamic acid

0.18 27.6 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid

0.644 31.6 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(4-(hydroxymethyl)thiazol-2-yl)ethyl)phenylsulfamic acid

0.167 50 (S)-4-(2-tert-Butoxycarbonylamino)-2-(4-(2-ethoxy-2-oxoethyl)thiazol-2-yl)ethyl)phenylsulfamic acid

0.132 50 (S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(2-(2-methoxy-2-oxoyethylamino)-2-oxoethyl)thiazole-2-yl)ethyl)phenylsulfamic acid

0.555 9.12 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(2-pivalamidothaizol-4-yl)ethyl)phenylsulfamic acid

0.308 11.4 (S)-4-(2-(tert-Butoxycarbonylamino)-2-(5-phenylthiazol-2-yl)ethyl)-phenyl sulfamic acid

0.253 11.8 4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)-phenyl sulfamic acid

0.045 14.6 4-((S)-2-(tert-Butoxycarbonylamino)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenyl sulfamic acid

The Rat hindlimb model is used to evaluate angiogenic properties ofnovel HPTPb inhibitors. Specifically to determine if there is enhancedblood flow to the collateral dependent region of the leg post ischemiawhen the animal is in an exercise challenged state. The specificcompound accessed in this example is(4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid.

Rat Hindlimb Model of Collateral Development

Animal Selection

In an effort to control for variables affecting execution of treadmillrunning, rats are familiarized with exercising on the treadmill (tmill)a week prior to surgery. This consisted of the rat running on the tmillfor intermittent bouts totaling five minutes daily at speeds between20-25 m/sec and an elevation of 7°. Previous experience demonstratedthat animals that did not run well during the familiarization periodperformed just as poorly during subsequent blood flow determinations,possibly altering collateral blood flow measurements. Based on thisexperience, rats that did not perform well during the familiarizationperiod are not included in this study.

Surgical Procedures

An initial surgery is done to create hindlimb ischemia and implantosmotic pumps essentially as previously described with minoralterations. Briefly, adult male Sprague-Dawley rats (wt 340-390 grams)are first placed in an induction chamber with an O2 flow rate of 1 L/minand Isoflurane (ISO) at 2.5%, body temperature is maintained via aheating pad under the chamber. Following induction, animals aretransferred to a surgical mat and anesthesia is continued via anon-rebreathing circuit. A warming lamp is positioned above the rat anda rectal probe is placed to monitor the animal's body temperature. Thegroin areas bilaterally are clipped and prepared with alternatingBetadine and alcohol scrubs (3×) and a sterile drape is placed over therat. The left femoral artery is exposed through a skin incision andsubsequently ligated in two positions 1 cm apart; distal to the inguinalligament and proximal to the femoral circumflex artery. The skin isclosed using either skin staples or Vetbond. The same procedure isrepeated on the right side. Animals in the Continuous infusion groupshad an Alzet 2ML2 pump (already primed) inserted into the SubQ space ontheir backs which delivered either 15 mg/kg/d or 5 mg/kg/d of4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid, or Vehicle depending upon the treatment groups. Animals in theVEGF treatment group underwent an additional procedure for placement ofan osmotic pump (Alert™ model # 2004) on their neck. Prior toimplantation, osmotic pumps are filled with VEGF165 solution at a doseof 15 μg/kg/day, and primed overnight inside sterile saline beakers in awater bath (37° C.). Stretched PE50 catheters coated with PPG (Polypropylene glycol Aldrich # 20-235-5) are attached using steriletechnique and in accordance with manufacture's instructions theafternoon prior to surgery. For pump placement, an incision is made toexpose the right jugular vein, an area is tunneled SubQ from the rightside of the neck to the back and the pump is placed in the resultingSubQ pocket. The vessel is ligated with 4-0 silk, a cut is made in thevessel just distal to the tie and the catheter from the osmotic pump isthreaded down stream (approx 2 cm) and secured with a second tie. Theskin is closed in the same manner as above.

Blood Flow Assessment

Catheter Placement

Two weeks after the ligation surgery the rat underwent a second acutesurgery to place indwelling catheters for microsphere measurements. Ratsare anesthetized as described above. The animal is clipped, prepped, andEMLA cream is applied to each entry site. First an incision is madelongitudinally at the ventral base of the tail using a 10 blade. Atapered PE 50 catheter is inserted approximately 3 cm into the ventraltail artery and anchored into place. The end of the catheter is thenwrapped around the tail and tunneled SubQ over the back, exiting betweenthe shoulder blades. Following tail artery cannulation, a midline neckincision is made to expose the left carotid artery for occlusivecannulation. A tapered PE 50 catheter is placed 3 cm into the carotidand the distal end is tunneled SubQ, exiting between the shoulderblades. The neck is closed with either skin stables or Vetbond and EMLAcream is applied. The exit site is closed around the catheters with apurse string suture stitch. The ends of the catheters are cauterizedshut and the rat is allowed to recover from anesthesia for at least 4hours.

Treadmill Protocol and Microsphere Measurements

For blood flow measurements, rats are placed onto the treadmill and thecatheters are connected to extension tubing via 22 gage male-maleconnectors. For microsphere withdrawals and blood pressure measurements,the tail artery catheter is connected to a syringe (coated with tweenand heparin-), which is “T” Ed to a withdrawal pump and a pressuretransducer. The carotid catheter is used for injecting the microspheres.The rat began running at speed 20 m/min and an elevation of 7°. Oneminute into the run the pump is turned on at a rate of 0.5 ml/min, tenseconds later 0.5 ml (1×10⁶ spheres/mL) of florescent microspheres areinfused into the carotid line followed by a 0.5 ml flush over 30seconds. The pump is set to stop at 90 seconds. The tmill is stopped,the extension lines are replaced and the animal's lines are flushed, andthe animal allowed to rest. The syringe and lines are removed from thepump and the reference blood sample is place in a labeled tube forprocessing. The withdrawal syringe and extension lines are flushed 3times with 2% tween, waste is flushed the reference blood tube A newsyringe and lines are place on the pump and the procedure is repeatedwith the animal running at a faster speed, (25 m/min) and a differentmicrosphere color is injected. At the completion of the second run, theanimal is euthanized with 0.3 ml of Buthaneasia.

Tissue Harvesting and Analysis

Following euthanasia, tissues are removed, trimmed, weighed, recorded,and placed in marked tubes for processing. The samples are as followsfor both left and right side; Soleus, Plantaris, Gastroc, Red Quads, andKidneys. Blood samples are digested with 0.75 ml of 16 N KOH overnight.Tissue is digested with 5 ml of 4 N KOH overnight. Samples then vacuumfiltered using 8-micron polycarbonate filters, and the filter paper isplaced in a labeled vial with 1 ml of 2-ethoxyethyl acetate (2EEA).Following overnight digestion, samples are read using a blackpopypropolene plate on a fluorometer set on wavelengths 495-506 and534-552. Exactly 270 ml of sample is pipetted into each well. Anyfurther need for dilutions is noted on the animal's data sheet andcorrected for in the raw data fluorescence. Raw data is converted toblood flow in terms of ml/min/100 g of tissue by the equation ({(TissueFluorescence/Tissue Weight g)/(Reference Blood Fluorescence/Bloodwithdraw rate mL/min)}*100 g). Flow values for left and right legtissues are averaged together to create one value for each animal, aslong as even distribution is exhibited between the kidneys.

In this study the VEGF treatment groups had the expected significantimprovement in GPS blood flow over the Vehicle control groups. In termsof the hemodynamic data the only significant difference between any ofthe groups is observed in the blood pressures of the treatment groups.These pressures are actually lower than the VEGF and/or Vehicle groups,suggesting that perfusion pressures to the GPS would also be slightlylow. This means that any changes measured in blood flow are real notjust a calculation artifact. Blood flows from the SubQ ContinuousInfusion, showed a significant improvement in Calf blood flow ascompared to vehicle for both doses (5 mg/kg/d and 15 mg/kg/d) of thecompound. The data also revealed that the lower dose (5 mg/kg/d) did notelicit a maximal VEGF response, suggesting a possible dose dependencywith this compound.

The results of this experiment are summarized herein below. TABLE IXBlood Pressure and Heart Rate Continuous SubQ Infusion VEGF Low HighANOVA 15 μg/kg/d Vehicle 5 mg/kg/d 15 mg/kg/d p Value Blood PressurePre-Exercise 146 ± 2.5 141 ± 3.1 132 ± 3.9† 137 ± 4.5 NS Exercise 156 ±2.3 151 ± 4.6 142 ± 3.2† 144 ± 4.6 NS Post-Exercise 149 ± 2.8 148 ± 5.3135 ± 3.1 133 ± 3.7*† <0.05 Heart Rate Pre-Exercise 452 ± 29.5 463 ±18.1 429 ± 19.8 428 ± 13.5 NS Exercise 489 ± 10.0 577 ± 15.2 487 ± 10.1456 ± 13.0 NS Post-Exercise 476 ± 18.1 468 ± 15.9 465 ± 18.8 462 ± 14.8NS N 10 8 10 10Data expressed as mean ± SE. ANOVA analysis using Tukey's test*significantly different from Vehicle,†significantly different p < 0.05 vs VEGF

TABLE X Blood Flow and Body Weight Continuous SubQ Infusion VEGF LowHigh ANOVA 15 μg/kg/d Vehicle 5 mg/kg/d 15 mg/kg/d p Value Blood FlowDuring exercise Calf (GPS)  76 ± 1.1*  53 ± 14  69 ± 2.0*†  75 ± 1.7*<0.001 Kidney 296 ± 32.3 248 ± 24.9 318 ± 30.1 319 ± 37.9 NS WeightsInitial Body Wt 372 ± 3.6 369 ± 2.7 365 ± 4.8 364 ± 4.8 NS Ending Body421 ± 5.5 411 ± 5.5 413 ± 5.6 409 ± 5.5 NS Wt N 10 8 9 8Data expressed as mean ± SE. ANOVA analysis using Tukey's test*significantly different from Vehicle,†significantly different p < 0.05 vs VEGF

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm.”

All documents cited in the Detailed Description of the Invention are, inrelevant part, incorporated herein by reference; the citation of anydocument is not to be construed as an admission that it is prior artwith respect to the present invention. To the extent that any meaning ordefinition of a term in this document conflicts with any meaning ordefinition of the same term in a document incorporated by reference, themeaning or definition assigned to that term in this document shallgovern.

While particular embodiments of the present disclosure have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this disclosure.

1. A compound having the formula:

wherein R is a substituted or unsubstituted thiazolyl unit having theformula:

R⁴ and R⁵ are each independently chosen from: i) hydrogen; ii)substituted or unsubstituted C₁-C₆ linear, branched, or cyclic alkyl;iii) substituted or unsubstituted phenyl; iv) substituted orunsubstituted heteroaryl; or R⁴ and R⁵ can be taken together to form asaturated or unsaturated ring having from 5 to 7 atoms; saidsubstitutions are independently chosen from one or more C₁-C₆ linear,branched, or cyclic alkyl, halogen, hydroxyl, or cyano units; R⁶ is aunit chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₆linear, branched, or cyclic alkyl; iii) substituted or unsubstitutedphenyl; and iv) substituted or unsubstituted heteroaryl; R¹ is chosenfrom: i) hydrogen; ii) C₁-C₆ linear or branched alkyl; iii) substitutedor unsubstituted phenyl; or iv) substituted or unsubstituted benzyl; R²is chosen from: i) C₁-C₆ linear or branched alkyl; or ii) C₁-C₆ linearor branched alkoxy; R³ is hydrogen or C₁-C₄ linear or branched alkyl. 2.A compound according to claim 1, wherein R has the formula:


3. A compound according to claim 2, wherein R⁴ and R⁵ are each hydrogen.4. A compound according to claim 2, wherein R⁵ is hydrogen and R⁴ issubstituted or unsubstituted C₁-C₆ linear, branched, or cyclic alkyl. 5.A compound according to claim 4, wherein R⁴ is chosen from methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, cyclopropyl,n-hexyl, and cyclohexyl.
 6. A compound according to claim 4, wherein R⁴is chosen from units having the formulae —CH₂F, —CHF₂, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, —CH₂Cl, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂NH₂,—CH₂NHCH₃, —CH₂N(CH₃)₂, and —CH₂NH(CH₂CH₃).
 7. A compound according toclaim 4, wherein R⁴ is 2,2-difluorocyclopropyl, 2-methoxycyclohexyl, or4-chlorocyclohexyl.
 8. A compound according to claim 2, wherein R⁵ ishydrogen and R⁴ is substituted or unsubstituted substituted orunsubstituted phenyl.
 9. A compound according to claim 8, wherein R⁴ ischosen from phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl,4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl,4-methoxyphenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl,3-chloropheny, 4-chlorophenyl, and 3,4-dichlorophenyl.
 10. A compoundaccording to claim 2, wherein R⁵ is hydrogen and R⁴ is substituted orunsubstituted heteroaryl.
 11. A compound according to claim 10, whereinR⁴ is a substituted or unsubstituted heteroaryl unit, said heteroarylunit chosen from 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl,[1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl, [1,2,4]triazol-4-yl,[1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl,pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl,isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.
 12. A compound according to claim 11, wherein R⁴is chosen from furan-2-yl, thiophene-2-yl, 5-chlorothiophene-2-yl, and5-methylthiophene-2-yl.
 13. A compound according to claim 1, wherein Ris a unit wherein R⁴ and R⁵ are taken together to form a saturated orunsaturated ring having from 5 to 7 atoms.
 14. A compound according toclaim 13, wherein R is 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl or4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl.
 15. A compound according toclaim 1, wherein R units have the formula


16. A compound according to claim 15, wherein R⁶ is hydrogen.
 17. Acompound according to claim 15, wherein R⁶ is chosen from methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. 18.A compound according to claim 15, wherein R⁶ is substituted orunsubstituted phenyl.
 19. A compound according to claim 18, wherein R⁶is chosen from include phenyl, 2-fluorophenyl, 2-chlorophenyl,2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,4-methylphenyl, and 4-methoxyphenyl.
 20. A compound according to claim15, wherein R⁶ is a substituted or unsubstituted heteroaryl unit, saidheteroaryl unit chosen from 1,2,3,4-tetrazol-1-yl,1,2,3,4-tetrazol-5-yl, [1,2,3]triazol-4-yl, [1,2,3]triazol-5-yl,[1,2,4]triazol-4-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl,pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl,thiophene-2-yl, thiophene-3-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,[1,2,4]thiadiazol-3-yl, [1,2,4]thiadiazol-5-yl, and[1,3,4]thiadiazol-2-yl.
 21. A compound according to claim 20, wherein R⁶is chosen from thiophene-2-yl, thiophene-3-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, 2,5-dimethylthiazol-4-yl,2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, and 3-methyl-1,2,4-oxadiazol-5-yl.
 22. A compound accordingto claim 15, wherein R has the formula:

R⁷ is C₁-C₄ substituted or unsubstituted alkyl and substituted orunsubstituted phenyl.
 23. A compound according to claim 22, wherein R⁶is 4-chlorobenzenesulfonylmethyl or tert-butylsulfonylmethyl.
 24. Acompound according to claim 1, wherein R¹ is hydrogen.
 25. A compoundaccording to claim 1, wherein R¹ is substituted or unsubstituted phenylor benzyl.
 25. A compound according to claim 25, wherein R¹ is benzyl.26. A compound according to claim 1, wherein R¹ is C₁-C₆ linear orbranched alkyl.
 27. A compound according to claim 26, wherein R¹ isiso-propyl.
 28. A compound according to claim 1, wherein R² is a C₁-C₆linear or branched alkoxy unit having the formula:—OR⁸ wherein R⁸ is a C₁-C₆ linear or branched alkyl unit chosen frommethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, or n-hexyl.
 29. A compound according to claim 28,wherein R⁸ is methyl, ethyl, or tert-butyl.
 30. A compound according toclaim 1, wherein R² is a C₁-C₆ linear or branched alkyl unit.
 31. Acompound according to claim 1, wherein R³ is hydrogen or methyl.
 32. Acompound according to claim 31, wherein R³ is hydrogen.
 33. A compoundhaving the formula:

wherein R² is chosen from: i) C₁-C₆ linear or branched alkyl; or ii)C₁-C₆ linear or branched alkoxy; R⁴ and R⁵ are each independently chosenfrom: i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear,branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv)substituted or unsubstituted heteroaryl; or R⁴ and R⁵ can be takentogether to form a saturated or unsaturated ring having from 5 to 7atoms.
 34. A compound having the formula:

wherein R² is chosen from: i) C₁-C₆ linear or branched alkyl; or ii)C₁-C₆ linear or branched alkoxy; R⁶ is chosen from: i) hydrogen; ii)substituted or unsubstituted C₁-C₆ linear, branched, or cyclic alkyl;iii) substituted or unsubstituted phenyl; and iv) substituted orunsubstituted heteroaryl.
 35. A compound having the formula:

wherein R² is chosen from: i) C₁-C₆ linear or branched alkyl; or ii)C₁-C₆ linear or branched alkoxy; R⁴ and R⁵ are each independently chosenfrom: i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear,branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv)substituted or unsubstituted heteroaryl; or R⁴ and R⁵ can be takentogether to form a saturated or unsaturated ring having from 5 to 7atoms.
 36. A compound having the formula:

wherein R² is chosen from: i) C₁-C₆ linear or branched alkyl; or ii)C₁-C₆ linear or branched alkoxy; R⁶ is chosen from: i) hydrogen; ii)substituted or unsubstituted C₁-C₆ linear, branched, or cyclic alkyl;iii) substituted or unsubstituted phenyl; and iv) substituted orunsubstituted heteroaryl.
 37. A compound having the formula:

wherein R² is chosen from: i) C₁-C₆ linear or branched alkyl; or ii)C₁-C₆ linear or branched alkoxy; R⁴ and R⁵ are each independently chosenfrom: i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear,branched, or cyclic alkyl; iii) substituted or unsubstituted phenyl; iv)substituted or unsubstituted heteroaryl; or R⁴ and R⁵ can be takentogether to form a saturated or unsaturated ring having from 5 to 7atoms.
 38. A compound having the formula:

wherein R² is chosen from: i) C₁-C₆ linear or branched alkyl; or ii)C₁-C₆ linear or branched alkoxy; R⁶ is chosen from: i) hydrogen; ii)substituted or unsubstituted C₁-C₆ linear, branched, or cyclic alkyl;iii) substituted or unsubstituted phenyl; and iv) substituted orunsubstituted heteroaryl.
 39. A compound chosen from;4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[(R)-2-(tert-Butoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid;{1-[1-(5-Ethylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethylcarbamoyl]-(S)-2-phenylethyl}methylcarbamic acid tert-butyl ester;{(S)-2-Phenyl-1-[1-(2-phenylthiazol-2-yl)-(S)-2-(4-sulfoaminophenyl)ethyl-carbamoyl]ethyl}carbamicacid tert-butyl ester4-{(S)-2-(S)-2-(tert-Butoxycarbonyl)-3-phenylpropaneamido-2-(2-phenylthiazole-4-yl)}phenylsulfamicacid;4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(thiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-methylthiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-propylthiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-(4-Cyclopropylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-(4-Cyclohexylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid;4-{(S)-2-(4,5-Dimethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid;4-{(S)-2-(4-Ethyl-5-methylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido)-2-[4-(3,3,3-trifluoropropyl)thiazol-2-yl]ethyl}phenylsulfamicacid;4-{(S)-2-[4-(2,2-Difluorocyclopropyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(methoxy-methyl)thiazol-2-yl]ethyl}phenylsulfamicacid;4-{(S)-2-(4-(Ethoxycarbonyl)thiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(5-phenylthiazol-2-yl))ethyl}phenylsulfamicacid;4-{(S)-2-(4-tert-Butylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid;4-{(S)-2-(4-Ethyl-5-phenylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenyl-propanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[4-(3,4-Dimethylphenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4-phenylthiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(thiophen-2-yl)thiazol-2-yl]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl}phenylsulfamicacid;4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropion-amido]ethyl}phenylsulfamicacid;4-{(S)-2-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[4-(5-Chlorothiophen-2-yl)thiazol-2-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Ethoxycarbonyl)-3-phenylpropanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-ethylthiazol-4-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-methylthiazol-4-yl)ethyl}phenylsulfamicacid;4-{(S)-2-(2-Ethylthiazole-4-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropan-amido]ethyl}phenylsulfamicacid;4-{(S)-2-(2-Isopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropan-amido]ethyl}phenylsulfamicacid;4-{(S)-2-(2-Cyclopropylthiazol-4-yl)-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-{2-[(4-Chlorophenylsulfonyl)methyl]thiazol-4-yl}-2-[(S)-2-(methoxy-carbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[2-(tert-Butylsulfonylmethyl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropionamido]-2-(2-phenylthiazole-4-yl)ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid;4-{(S)-2-[2-(3-Chlorothiophen-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(3-methylthiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid;4-{[(S)-2-(2-(Furan-2-yl)thiazol-4-yl]-2-[(S)-2-(methoxycarbonyl)-3-phenylpropanamido]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(2-methylthiazole-4-yl)thiazole-4-yl]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-(2-pyrazine-2-yl)thiazole-4-yl}phenylsulfamicacid; and4-{(S)-2-[(S)-2-(Methoxycarbonyl)-3-phenylpropanamido]-2-[2-(6-methylpyridin-3-yl)thiazol-4-yl]ethyl}phenylsulfamicacid.
 40. A compound chosen from:4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-ethylthiazol-2-yl)ethyl]phenylsulfamicacid;4-[(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-(4-tert-butylthiazol-2-yl)ethyl]phenylsulfamicacid;4-{(S)-2-((S)-2-Acetamido-3-phenylpropanamido)-2-[4-(thiophen-3-yl)thiazol-2-yl]ethyl)phenylsulfamicacid;4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-3-methylbutanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid;(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}phenyl-sulfamicacid;(S)-4-{2-(4-Ethylthiazol-2-yl)-2-[2-(methoxycarbonyl)acetamido]ethyl}phenyl-sulfamicacid;4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-3-methylbutanamido]-ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-(4-ethylthiazol-2-yl)ethyl}phenylsulfamicacid;4-{(S)-2-(4-Ethylthiazol-2-yl)-2-[(S)-2-(methoxycarbonyl)-4-methylpentan-amido]ethyl}phenylsulfamicacid;4-((S)-2-(4-Ethylthiazol-2-yl)-2-{(S)-2-[2-(methoxycarbonyl)acetamide]-3-phenylpropanamido}ethyl)phenylsulfamicacid;4-{(S)-2-[(S)-2-(tert-Butoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid;4-{(S)-2-[(S)-2-(Methoxycarbonyl)-4-methylpentanamido]-2-[2-(thiophen-2-yl)thiazol-4-yl]ethyl}phenylsulfamicacid; and(S)-4-{2-[2-(tert-Butoxycarbonyl)acetamide]-2-(4-ethylthiazol-2-yl)ethyl}-phenylsulfamicacid.
 41. A compound having the formula:

wherein R is a substituted or unsubstituted thiazolyl unit having theformula:

R⁴ and R⁵ are each independently chosen from: i) hydrogen; ii)substituted or unsubstituted C₁-C₆ linear, branched, or cyclic alkyl;iii) substituted or unsubstituted phenyl; iv) substituted orunsubstituted heteroaryl; or R⁴ and R⁵ can be taken together to form asaturated or unsaturated ring having from 5 to 7 atoms; saidsubstitutions are independently chosen from one or more C₁-C₆ linear,branched, or cyclic alkyl, halogen, hydroxyl, or cyano units; R⁶ is aunit chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₆linear, branched, or cyclic alkyl; iii) substituted or unsubstitutedphenyl; and iv) substituted or unsubstituted heteroaryl; R¹ is chosenfrom: i) hydrogen; ii) C₁-C₆ linear or branched alkyl; iii) substitutedor unsubstituted phenyl; or iv) substituted or unsubstituted benzyl; R²is chosen from: i) C₁-C₆ linear or branched alkyl; or ii) C₁-C₆ linearor branched alkoxy; R³ is hydrogen or C₁-C₄ linear or branched alkyl.42. A compound chosen from:[1-(S)-(Phenylthiazol-2-yl)-2-(4-sulfoaminophenyl)ethyl]-carbamic acidtert-butyl ester;(S)-4-(2-(4-Methylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamic acid;(S)-4-(2-(4-Ethylthiazole-2-yl)-2-pivalamideoethyl)phenylsulfamic acid;(S)—N-(1-(4-Hydroxymethyl)thiazole-2-yl)-2pivalamidoethyl)phenylsulfamicacid;(S)-4-(2-(4-Ethoxycarbonyl)thiazole-2-yl)-2-pivalamideoethyl)phenylsulfamicacid; (S)-4-(2-(4-Phenylthiazole-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;4-((S)-2-(4-(3-Methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;N—((S)-1-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(4-nitrophenyl)ethyl)pivalamide;4-((S)-2-(4-(3-methoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;4-((S)-2-(4-(2,4-Dimethoxyphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenyl-sulfamicacid; (S)-4-(2-(4-benzylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;(S)-4-(2-Pivalamido-2-(4-(thiophen-2-ylmethyl)thiazol-2-yl)ethyl)phenylsulfamicacid;(S)-4-(2-(4-(3-Methoxybenzyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;4-((S)-2-(4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;(S)-4-(2-(5-Methyl-4-phenylthiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;(S)-4-(2-(4-(4-Biphenyl)thiazol-2-yl)-2-pivalamidoethyl)phenylsulfamicacid;(S)-4-(2-tert-Butoxycarbonyl-2-(2-methylthaizole-4-yl)-phenylsulfamicacid(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-propylthiazol-2-yl)ethyl)-phenylsulfamic acid;(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-tert-butylthiazol-2-yl)ethyl)-phenylsulfamic acid;(S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(methoxymethyl)thiazol-2-yl)ethyl)-phenylsulfamic acid; (S)-tert-Butyl2-(4-nitrophenyl)-1-(4-(trifluoromethyl)thiazol-2-yl)ethylcarbamate;(S)-4-(2-tert-Butoxycarbonyl)-2-(4-(2-hydroxymethyl)thiazole-2yl)ethyl)phenylsulfamicacid;(S)-4-(2-tert-Butoxycarbonyl)-2-(4-(2-ethoxy-2-oxoethyl)-thiazole-2-yl)-ethyl)phenylsulfamicacid; (S)-4-(2-(tert-Butoxycarbonyl)-2-(4-(2-(2-methoxy-2-oxoyethylamino)-2-oxoethyl)thiazole-2-yl)ethyl)phenylsulfamic acid;(S)-4-(2-(tert-Butoxycarbonyl)-2-(2-pivalamidothiazole-4-yl)ethyl)phenyl-sulfamicacid;(S)-4-(2-(tert-Butoxycarbonyl)-2-(5-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid;4-((S)-2-(tert-Butoxycarbonyl)-2-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)ethyl)-phenylsulfamic acid;(S)-4-(2-(tert-Butoxycarbonyl)-2-(5-phenylthiazol-2-yl)ethyl)-phenylsulfamic acid;(S)-{4-[2,2-Dimethyl-propionylamino)-2-(2-phenyl-thiazole-4-yl)ethyl]phenyl}-sulfamicacid;(S)-4-(2-tert-Butoxycarbonyl)-2-(4-phenyl)-2-(4-phenylthiazole-2-yl)-ethyl)-phenylsulfamicacid;(S,S)-2-(2-{2-[1-tert-Butoxycarbonylamino-2-(4-sulfoamino-phenyl)-ethyl]-thiazole-4-yl}-acetylamino-3-phenyl-propionicacid methyl ester;(S)-[1-{1-Oxo-4-[2-(1-phenyl-1H-tetrazole-5-sulfonylethyl]-1H-1λ⁴-thiazole-2-yl}-2-(4-sulfamino-phenyl)-ethyl]-carbamicacid tert-butyl ester;4-((S)-2-(tert-Butoxycarbonyl)-2-(4-(thiophen-3-yl)thiazol-2-yl)ethyl)phenylsulfamic acid;(S)-4-(2-(Benzo[d]thiazol-2-yl)-2-(tert-butoxycarbonyl)ethyl)phenylsulfamicacid; and(S)-4-(2-tert-Butoxycarbonyl-2-(2-methylthaizole-4-yl)-phenylsulfamicacid.
 43. A pharmaceutical composition comprising: A) one or morecompounds according to claim 1; and B) one or more excipients orcarriers.
 44. A method for treating a disease chosen from a disorderchosen from diabetic retinopathy, macular degeneration, cancer, sicklecell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget'sdisease, vein occlusion, artery occlusion, carotid obstructive disease,chronic uveitis/vitritis, mycobacterial infections, Lyme's disease,systemic lupus erythematosis, retinopathy of prematurity, Eales'disease, Behcet's disease, infections causing a retinitis orchoroiditis, presumed ocular histoplasmosis, Best's disease, myopia,optic pits, Stargardt's disease, pars planitis, chronic retinaldetachment, hyperviscosity syndrome, toxoplasmosis, trauma andpost-laser complications, diseases associated with rubeosis, andproliferative vitreoretinopathy comprising administering to a human acompound according to claim
 1. 45. A method for treating a diseasechosen from a disorder chosen from Crohn's disease and ulcerativecolitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangiomas,Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia,solid or blood borne tumors and acquired immune deficiency syndromecomprising administering to a human a compound according to claim
 1. 46.A method for treating a disease chosen from a disorder chosen fromskeletal muscle and myocardial ischemia, stroke, coronary arterydisease, peripheral vascular disease, coronary artery disease comprisingadministering to a human a compound according to claim
 1. 47. A methodfor regulating angiogenesis in a human comprising administering to ahuman a compound according to claim
 1. 48. A method for vascularizingischemic tissue in a human comprising administering to a human acompound according to claim
 1. 49. A method for promoting the growth ofskin graft replacements comprising administering to a human a compoundaccording to claim
 1. 50. A method for promoting tissue repair in thecontext of guided tissue regeneration (GTR) procedures comprisingadministering to a human a compound according to claim
 1. 51. A compoundhaving the formula:

wherein R is a substituted or unsubstituted thiazolyl unit having theformula:

R² is chosen from: i) C₁-C₆ linear or branched alkyl; or ii) C₁-C₆linear or branched alkoxy; R⁴ and R⁵ are each independently chosen from:i) hydrogen; ii) substituted or unsubstituted C₁-C₆ linear, branched, orcyclic alkyl; iii) substituted or unsubstituted phenyl; iv) substitutedor unsubstituted heteroaryl; or R⁴ and R⁵ can be taken together to forma saturated or unsaturated ring having from 5 to 7 atoms.
 52. Apharmaceutical composition comprising: A) one or more compoundsaccording to any of claims 33-38 and 51; and B) one or more excipientsor carriers.
 53. A method for treating a disease chosen from a disorderchosen from diabetic retinopathy, macular degeneration, cancer, sicklecell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget'sdisease, vein occlusion, artery occlusion, carotid obstructive disease,chronic uveitis/vitritis, mycobacterial infections, Lyme's disease,systemic lupus erythematosis, retinopathy of prematurity, Eales'disease, Behcet's disease, infections causing a retinitis orchoroiditis, presumed ocular histoplasmosis, Best's disease, myopia,optic pits, Stargardt's disease, pars planitis, chronic retinaldetachment, hyperviscosity syndrome, toxoplasmosis, trauma andpost-laser complications, diseases associated with rubeosis, andproliferative vitreoretinopathy comprising administering to a human acompound according to any of claims 33-38 and
 51. 54. A method fortreating a disease chosen from a disorder chosen from Crohn's diseaseand ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis,hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagictelangiectasia, solid or blood borne tumors and acquired immunedeficiency syndrome comprising administering to a human a compoundaccording to any of claims 33-38 and
 51. 55. A method for treating adisease chosen from a disorder chosen from skeletal muscle andmyocardial ischemia, stroke, coronary artery disease, peripheralvascular disease, coronary artery disease comprising administering to ahuman a compound according to any of claims 33-38 and
 51. 56. A methodfor regulating angiogenesis in a human comprising administering to ahuman a compound according to any of claims 33-38 and
 51. 57. A methodfor vascularizing ischemic tissue in a human comprising administering toa human a compound according to any of claims 33-38 and
 51. 58. A methodfor promoting the growth of skin graft replacements comprisingadministering to a human a compound according to any of claims 33-38 and51.
 59. A method for promoting tissue repair in the context of guidedtissue regeneration (GTR) procedures comprising administering to a humana compound according to any of claims 33-38 and
 51. 60. A compoundaccording to any of claims 1, 33-38 and 51, wherein the compound is apharmaceutically acceptable of either basic groups or acid groups.
 61. Acompound according to claim 60, wherein the compounds are saltscomprising anions chosen from chloride, bromide, iodide, sulfate,bisulfate, carbonate, bicarbonate, phosphate, formate, acetate,propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate,succinate, tartrate, fumarate, and citrate.
 62. A compound according toclaim 60, wherein the compounds are salts comprising cations chosen fromsodium, lithium, potassium, calcium, magnesium, and bismuth.